0A4F4F9BD490A749D5437F821CF06DF1
21 CFR 320
https://www.govinfo.gov/content/pkg/CFR-2012-title21-vol5/pdf/CFR-2012-title21-vol5-part320.pdf
http://leaux.net/URLS/ConvertAPI Text Files/C674F39B00C3F7BA20AD108CD7092CE3.en.txt
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| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / Indigenous
Searching for indicator native:
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p.000195:
p.000195:
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p.000195:
p.000195: § 320.25
p.000195: outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the ap- proaches described
p.000195: in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of this section are not available. This ap-
p.000195: proach may also be considered suffi- ciently accurate for measuring bio- availability or
p.000195: demonstrating bio- equivalence of dosage forms intended to deliver the active moiety locally, e.g.,
p.000195: topical preparations for the skin, eye, and mucous membranes; oral dos- age forms not intended to be
p.000195: absorbed, e.g., an antacid or radiopaque medium; and bronchodilators administered by inhalation if the onset
p.000195: and duration of pharmacological activity are defined.
p.000195: (5) A currently available in vitro test
p.000195: acceptable to FDA (usually a dissolu- tion rate test) that ensures human in vivo bioavailability.
p.000195: (6) Any other approach deemed ade- quate by FDA to measure bio- availability or
p.000195: establish bioequiva- lence.
p.000195: (c) FDA may, notwithstanding prior requirements for measuring bio- availability or establishing
p.000195: bioequiva- lence, require in vivo testing in hu- mans of a product at any time if the agency has
p.000195: evidence that the product:
p.000195: (1) May not produce therapeutic ef- fects comparable to a pharmaceutical equivalent or alternative with which
p.000195: it is intended to be used interchangeably;
p.000195: (2) May not be bioequivalent to a pharmaceutical equivalent or alter- native with which it is
p.000195: intended to be used interchangeably; or
p.000195: (3) Has greater than anticipated po- tential toxicity related to pharmaco- kinetic or other characteristics.
p.000195: [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July
p.000195: 1, 1992, as amended at 67 FR 77673, Dec. 19,
p.000195: 2002]
p.000195:
p.000195: § 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000195: (a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no
p.000195: unnecessary human re- search should be done.
p.000195: (2) An in vivo bioavailability study is generally done in a normal adult popu- lation under standardized
p.000195: conditions. In some situations, an in vivo bio- availability study in humans may pref- erably and more
p.000195: properly be done in suitable patients. Critically ill patients
p.000195: 21 CFR Ch. I (4–1–12 Edition)
p.000195: shall not be included in an in vivo bio- availability study unless the attending physician determines that there
p.000195: is a potential benefit to the patient.
p.000195: (b) Basic design. The basic design of an in vivo bioavailability study is de- termined by the following:
p.000195: (1) The scientific questions to be an- swered.
p.000195: (2) The nature of the reference mate- rial and the dosage form to be tested.
p.000195: (3) The availability of analytical methods.
p.000195: (4) Benefit-risk considerations in re- gard to testing in humans.
p.000195: (c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in
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Political / political affiliation
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p.000203: 203
p.000203:
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p.000203:
p.000203:
p.000203: § 320.35
p.000203: batches that were tested by the Food and Drug Administration and found to meet the bioequivalence
p.000203: requirement, unless the public health requires that batch testing be extended to additional batches.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992]
p.000203:
p.000203: § 320.35 Requirements for in vitro test- ing of each batch.
p.000203: If a bioequivalence requirement specifies a currently available in vitro test or an in
p.000203: vitro bioequivalence standard comparing the drug product to a reference standard, the manufac- turer shall
p.000203: conduct the test on a sam- ple of each batch of the drug product to assure batch-to-batch uniformity.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992]
p.000203:
p.000203: § 320.36 Requirements for mainte- nance of records of bioequivalence testing.
p.000203: (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure
p.000203: that the product meets a bioequivalence re- quirement shall be maintained by the manufacturer for at
p.000203: least 2 years after the expiration date of the batch and submitted to the Food and Drug Ad- ministration
p.000203: on request.
p.000203: (b) Any person who contracts with another party to conduct a bioequiva- lence study from which the data are
p.000203: in- tended to be submitted to FDA as part of an application submitted under part
p.000203: 314 of this chapter shall obtain from the person conducting the study suffi- cient accurate financial
p.000203: information to allow the submission of complete and accurate financial certifications or dis- closure statements
p.000203: required under part
p.000203: 54 of this chapter and shall maintain that information and all records relat- ing to the compensation
p.000203: given for that study and all other financial interest information required under part 54 of this chapter
p.000203: for 2 years after the date of approval of the application. The per- son maintaining these records shall,
p.000203: upon request for any properly author- ized officer or employee of the Food and Drug Administration, at
p.000203: reason- able time, permit such officer or em-
p.000203: 21 CFR Ch. I (4–1–12 Edition)
p.000203: ployee to have access to and copy and verify these records.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992, as amended at 63 FR
p.000203: 5252, Feb. 2, 1998]
p.000203:
p.000203: § 320.38 Retention of bioavailability samples.
p.000203: (a) The applicant of an application or supplemental application submitted under section 505 of the Federal
p.000203: Food, Drug, and Cosmetic Act, or, if bio- availability testing was performed under contract,
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p.000204: the sam- ple from which the reserve sample was obtained was used.
p.000204: (f) Authorized FDA personnel will or- dinarily collect reserve samples di- rectly from the applicant or
p.000204: contract research organization at the storage site during a preapproval inspection. If authorized FDA
p.000204: personnel are unable to collect samples, FDA may require the applicant or contract research or- ganization
p.000204: to submit the reserve sam- ples to the place identified in the agen- cy’s request. If FDA has not collected
p.000204: or requested delivery of a reserve sam- ple, or if FDA has not collected or re- quested delivery of any
p.000204: portion of a re- serve sample, the applicant or contract research organization shall retain the sample or
p.000204: remaining sample for the 5- year period specified in paragraph (e) of this section.
p.000204: (g) Upon release of the reserve sam-
p.000204: ples to FDA, the applicant or contract research organization shall provide a written assurance that, to
p.000204: the best knowledge and belief of the individual executing the assurance, the reserve samples came
p.000204: from the same samples
p.000204:
p.000204: as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall
p.000204: be exe- cuted by an individual authorized to act for the applicant or contract re- search organization in
p.000204: releasing the re- serve samples to FDA.
p.000204: (h) A contract research organization may contract with an appropriate, independent third party
p.000204: to provide storage of reserve samples provided that the sponsor of the study has been notified in
p.000204: writing of the name and ad- dress of the facility at which the re- serve samples will be stored.
p.000204: (i) If a contract research organization conducting a bioavailability or bio- equivalence study that requires
p.000204: reserve sample retention under this section or
p.000204: § 320.63 goes out of business, it shall transfer its reserve samples to an ap- propriate, independent
p.000204: third party, and shall notify in writing the sponsor of the study of the transfer and provide the study
p.000204: sponsor with the name and address of the facility to which the re- serve samples have been transferred.
p.000204: [58 FR 25927, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000204:
p.000204: § 320.63 Retention of bioequivalence samples.
p.000204: The applicant of an abbreviated ap- plication or a supplemental application submitted under section 505 of the
p.000204: Fed- eral Food, Drug, and Cosmetic Act, or, if bioequivalence testing was per- formed under contract,
p.000204: the contract re- search organization shall retain re- serve samples of any test article and reference
p.000204: standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the ab-
p.000204: breviated application or supplemental application. The applicant or contract research organization shall
p.000204: retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall
p.000204: release the reserve samples to FDA upon request in accordance with
p.000204: § 320.38.
p.000204: [58 FR 25928, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000205: 205
p.000205:
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p.000205:
p.000205:
p.000205: Pt. 328
p.000205: PART 328—OVER-THE-COUNTER DRUG PRODUCTS INTENDED FOR ORAL INGESTION THAT CONTAIN ALCOHOL
p.000205: Subpart A—General Provisions
p.000205: Sec.
p.000205: 328.1 Scope.
p.000205: 328.3 Definitions.
p.000205: Subpart B—Ingredients
p.000205: 328.10 Alcohol.
p.000205: Subpart C—Labeling
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Political / stateless persons
Searching for indicator nation:
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p.000194: product. Applicants shall conduct bio- availability and bioequivalence testing using the most accurate,
p.000194: sensitive, and reproducible approach available among those set forth in paragraph (b) of this section. The
p.000194: method used must be ca- pable of measuring bioavailability or establishing bioequivalence, as appro- priate,
p.000194: for the product being tested.
p.000194: (b) The following in vivo and in vitro approaches, in descending order of ac- curacy, sensitivity, and
p.000194: reproduc- ibility, are acceptable for determining the bioavailability or bioequivalence of a drug product.
p.000194: (1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety,
p.000194: and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological
p.000194: fluid is meas- ured as a function of time. This ap- proach is particularly applicable to dosage
p.000194: forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body;
p.000194: or
p.000194:
p.000194: (ii) An in vitro test that has been correlated with and is predictive of human in vivo
p.000194: bioavailability data; or
p.000194: (2) An in vivo test in humans in which the urinary excretion of the ac- tive moiety, and, when
p.000194: appropriate, its active metabolite(s), are measured as a function of time. The intervals at which
p.000194: measurements are taken should ordinarily be as short as possible so that the measure of the rate of
p.000194: elimi- nation is as accurate as possible. De- pending on the nature of the drug prod- uct, this approach may be
p.000194: applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section. This
p.000194: method is not appropriate where urinary excretion is not a significant mechanism of elimination.
p.000194: (3) An in vivo test in humans in
p.000194: which an appropriate acute pharma- cological effect of the active moiety, and, when appropriate, its
p.000194: active me- tabolite(s), are measured as a function of time if such effect can be measured with
p.000194: sufficient accuracy, sensitivity, and reproducibility. This approach is applicable to the category of
p.000194: dosage forms described in paragraph (b)(1)(i) of this section only when appropriate methods are not
p.000194: available for measure- ment of the concentration of the moi- ety, and, when appropriate, its active
p.000194: metabolite(s), in biological fluids or ex- cretory products but a method is avail- able for the measurement of an
p.000194: appro- priate acute pharmacological effect. This approach may be particularly ap- plicable to dosage
p.000194: forms that are not intended to deliver the active moiety to the bloodstream for systemic dis-
p.000194: tribution.
p.000194: (4) Well-controlled clinical trials that
p.000194: establish the safety and effectiveness of the drug product, for purposes of measuring
p.000194: bioavailability, or appro- priately designed comparative clinical trials, for purposes of demonstrating
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Health / Drug Usage
Searching for indicator drug:
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p.000190:
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p.000190:
p.000190: § 316.52
p.000190: Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
p.000190: [65 FR 56480, Sept. 19, 2000]
p.000190:
p.000190: 21 CFR Ch. I (4–1–12 Edition)
p.000190: PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
p.000190: Subpart A—General Provisions
p.000190:
p.000190: § 316.52 Availability for public disclo- sure of data and information in re- quests and applications.
p.000190: (a) FDA will not publicly disclose the existence of a request for orphan-drug designation under section 526 of the
p.000190: act prior to final FDA action on the re- quest unless the existence of the re- quest has been
p.000190: previously publicly dis- closed or acknowledged.
p.000190: (b) Whether or not the existence of a pending request for designation has been publicly disclosed
p.000190: or acknowl- edged, no data or information in the re- quest are available for public disclo- sure prior to
p.000190: final FDA action on the request.
p.000190: (c) Upon final FDA action on a re- quest for designation, FDA will deter- mine the public
p.000190: availability of data and information in the request in ac- cordance with part 20 and § 314.430 of this
p.000190: chapter and other applicable stat- utes and regulations.
p.000190: (d) In accordance with § 316.28, FDA will make a cumulative list of all or- phan drug designations
p.000190: available to the public and update such list monthly.
p.000190: (e) FDA will not publicly disclose the existence of a pending marketing appli- cation for a designated orphan drug for
p.000190: the use for which the drug was des- ignated unless the existence of the ap- plication has been
p.000190: previously publicly disclosed or acknowledged.
p.000190: (f) FDA will determine the public availability of data and information contained in pending
p.000190: and approved marketing applications for a des- ignated orphan drug for the use for which
p.000190: the drug was designated in ac- cordance with part 20 and § 314.430 of this chapter and other applicable
p.000190: stat- utes and regulations.
p.000190: Sec.
p.000190: 320.1 Definitions.
p.000190: Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products
p.000190: 320.21 Requirements for submission of bio- availability and bioequivalence data.
p.000190: 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.
p.000190: 320.23 Basis for measuring in vivo bio- availability or demonstrating bioequiva- lence.
p.000190: 320.24 Types of evidence to measure bio- availability or establish bioequivalence.
p.000190: 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000190: 320.26 Guidelines on the design of a single- dose in vivo bioavailability or bioequiva- lence study.
p.000190: 320.27 Guidelines on the design of a mul- tiple-dose in vivo bioavailability study.
p.000190: 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical evidence.
p.000190: 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study.
p.000190: 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- view of protocols by
p.000190: the Food and Drug Administration.
p.000190: 320.31 Applicability of requirements regard- ing an ‘‘Investigational New Drug Appli- cation.’’
p.000190: 320.32 Procedures for establishing or amend- ing a bioequivalence requirement.
p.000190: 320.33 Criteria and evidence to assess actual or potential bioequivalence problems.
p.000190: 320.34 Requirements for batch testing and certification by the Food and Drug Ad- ministration.
p.000190: 320.35 Requirements for in vitro testing of each batch.
p.000190: 320.36 Requirements for maintenance of records of bioequivalence testing.
p.000190: 320.38 Retention of bioavailability samples.
p.000190: 320.63 Retention of bioequivalence samples. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371.
p.000190: Subpart A—General Provisions
p.000190: § 320.1 Definitions.
p.000190: (a) Bioavailability means the rate and extent to which the active ingredient or active moiety is
p.000190: absorbed from a drug product and becomes available at the site of action. For drug products that are
p.000190: not intended to be absorbed
p.000190: 190
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p.000190:
p.000190: Food and Drug Administration, HHS § 320.21
p.000190:
p.000190:
p.000190: into the bloodstream, bioavailability may be assessed by measurements in- tended to reflect the rate and
p.000190: extent to which the active ingredient or active moiety becomes available at the site of action.
p.000190: (b) Drug product means a finished dos- age form, e.g., tablet, capsule, or solu- tion, that contains the
p.000190: active drug in- gredient, generally, but not nec- essarily, in association with inactive
p.000190: ingredients.
p.000190: (c) Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of
p.000190: the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic
p.000190: moiety, or, in the case of modified release dosage forms that re- quire a reservoir or overage or
p.000190: such forms as prefilled syringes where resid- ual volume may vary, that deliver identical amounts of the
p.000190: active drug ingredient over the identical dosing pe- riod; do not necessarily contain the same inactive
p.000190: ingredients; and meet the identical compendial or other ap- plicable standard of identity, strength,
p.000190: quality, and purity, including potency and, where applicable, content uni- formity, disintegration
p.000190: times, and/or dissolution rates.
p.000190: (d) Pharmaceutical alternatives means
p.000190: drug products that contain the iden- tical therapeutic moiety, or its pre- cursor, but not necessarily
p.000190: in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets
p.000190: either the identical or its own respective compendial or other applicable standard of identity,
p.000190: strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or
p.000190: dissolution rates.
p.000190: (e) Bioequivalence means the absence of a significant difference in the rate and extent to which the
p.000190: active ingre- dient or active moiety in pharma- ceutical equivalents or pharmaceutical alternatives becomes
p.000190: available at the site of drug action when administered at the same molar dose under similar conditions in
p.000190: an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain ex-
p.000190: tended release dosage forms), certain pharmaceutical equivalents or alter- natives may be considered
p.000190: bioequiva-
p.000190:
p.000190: lent if there is no significant difference in the extent to which the active ingre- dient or moiety from each
p.000190: product be- comes available at the site of drug ac- tion. This applies only if the difference in the rate at
p.000190: which the active ingre- dient or moiety becomes available at the site of drug action is intentional and
p.000190: is reflected in the proposed label- ing, is not essential to the attainment of effective body drug
p.000190: concentrations on chronic use, and is considered medi- cally insignificant for the drug.
p.000190: (f) Bioequivalence requirement means a
p.000190: requirement imposed by the Food and Drug Administration for in vitro and/or in vivo testing of specified drug
p.000190: prod- ucts which must be satisfied as a condi- tion of marketing.
p.000190: (g) Same drug product formulation means the formulation of the drug product submitted for
p.000190: approval and any formulations that have minor dif- ferences in composition or method of manufacture from
p.000190: the formulation sub- mitted for approval, but are similar enough to be relevant to the agency’s
p.000190: determination of bioequivalence.
p.000190: [42 FR 1634, Jan. 7, 1977, as amended at 42 FR
p.000190: 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67
p.000190: FR 77672, Dec. 19, 2002; 74 FR 2861, Jan. 16,
p.000190: 2009]
p.000190:
p.000190: Subpart B—Procedures for Deter- mining the Bioavailability or Bioequivalence of Drug Prod- ucts
p.000190: SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth-
p.000190: erwise noted.
p.000190:
p.000190: § 320.21 Requirements for submission of bioavailability and bioequiva- lence data.
p.000190: (a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall
p.000190: include in the application either:
p.000190: (1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application; or
p.000190: (2) Information to permit FDA to waive the submission of evidence meas- uring in vivo bioavailability.
p.000190: (b) Any person submitting an abbre- viated new drug application to FDA shall include in the
p.000190: application either:
p.000190: (1) Evidence demonstrating that the drug product that is the subject of the
p.000191: 191
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p.000191:
p.000191:
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p.000191:
p.000191:
p.000191:
p.000191: § 320.21
p.000191: abbreviated new drug application is bioequivalent to the reference listed drug (defined in §
p.000191: 314.3(b) of this chap- ter). A complete study report must be submitted for the bioequivalence study upon
p.000191: which the applicant relies for ap- proval. For all other bioequivalence studies conducted on the
p.000191: same drug product formulation, the applicant must submit either a complete or sum- mary report. If a
p.000191: summary report of a bioequivalence study is submitted and FDA determines that there may be bio- equivalence
p.000191: issues or concerns with the product, FDA may require that the ap- plicant submit a complete report of the
p.000191: bioequivalence study to FDA; or
p.000191: (2) Information to show that the drug
p.000191: product is bioequivalent to the ref- erence listed drug which would permit FDA to waive the
p.000191: submission of evi- dence demonstrating in vivo bioequiva- lence as provided in paragraph (f) of this section.
p.000191: (c) Any person submitting a supple- mental application to FDA shall in- clude in the supplemental
p.000191: application the evidence or information set forth in paragraphs (a) and (b) of this section if the
p.000191: supplemental application pro- poses any of the following changes:
p.000191: (1) A change in the manufacturing site or a change in the manufacturing process, including a change
p.000191: in product formulation or dosage strength, beyond the variations provided for in the ap- proved application.
p.000191: (2) A change in the labeling to pro- vide for a new indication for use of the drug product, if clinical
p.000191: studies are re- quired to support the new indication for use.
p.000191: (3) A change in the labeling to pro- vide for a new dosage regimen or for an additional dosage regimen for a
p.000191: special patient population, e.g., infants, if clin- ical studies are required to support the new or additional dosage
p.000191: regimen.
p.000191: (d) FDA may approve a full new drug application, or a supplemental applica- tion proposing any of the changes set
p.000191: forth in paragraph (c) of this section, that does not contain evidence of in vivo bioavailability or
p.000191: information to permit waiver of the requirement for in vivo bioavailability data, if all of the following
p.000191: conditions are met.
p.000191: (1) The application is otherwise ap- provable.
p.000191: 21 CFR Ch. I (4–1–12 Edition)
p.000191: (2) The application agrees to submit, within the time specified by FDA, ei- ther:
p.000191: (i) Evidence measuring the in vivo bioavailability and demonstrating the in vivo bioequivalence of
p.000191: the drug product that is the subject of the appli- cation; or
p.000191: (ii) Information to permit FDA to waive measurement of in vivo bio- availability.
p.000191: (e) Evidence measuring the in vivo bioavailability and demonstrating the in vivo bioequivalence of a drug
p.000191: prod- uct shall be obtained using one of the approaches for determining bio- availability set
p.000191: forth in § 320.24.
p.000191: (f) Information to permit FDA to waive the submission of evidence meas- uring the in vivo
p.000191: bioavailability or demonstrating the in vivo bioequiva- lence shall meet the criteria set forth in §
p.000191: 320.22.
p.000191: (g) Any person holding an approved full or abbreviated new drug applica- tion shall submit to FDA a
p.000191: supple- mental application containing new evi- dence measuring the in vivo bio- availability or
p.000191: demonstrating the in vivo bioequivalence of the drug product that is the subject of the application if notified by
p.000191: FDA that:
p.000191: (1) There are data demonstrating that the dosage regimen in the labeling is based on incorrect assumptions
p.000191: or facts regarding the pharmacokinetics of the drug product and that following this dosage regimen could
p.000191: potentially result in subtherapeutic or toxic levels; or
p.000191: (2) There are data measuring signifi- cant intra-batch and batch-to-batch variability, e.g., plus or
p.000191: minus 25 per- cent, in the bioavailability of the drug product.
p.000191: (h) The requirements of this section regarding the submission of evidence measuring the in vivo
p.000191: bioavailability or demonstrating the in vivo bio- equivalence apply only to a full or ab-
p.000191: breviated new drug application or a supplemental application for a finished dosage formulation.
p.000191: [57 FR 17998, Apr. 28, 1992, as amended at 67
p.000191: FR 77672, Dec. 19, 2002; 74 FR 2862, Jan. 16,
p.000191: 2009]
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p.000192:
p.000192:
p.000192: Food and Drug Administration, HHS § 320.22
p.000192:
p.000192:
p.000192: § 320.22 Criteria for waiver of evidence of in vivo bioavailability or bio- equivalence.
p.000192: (a) Any person submitting a full or abbreviated new drug application, or a supplemental application
p.000192: proposing any of the changes set forth in
p.000192: § 320.21(c), may request FDA to waive the requirement for the submission of evidence measuring the in
p.000192: vivo bio- availability or demonstrating the in vivo bioequivalence of the drug product that is the subject
p.000192: of the application. An applicant shall submit a request for waiver with the application. Except as provided in
p.000192: paragraph (f) of this sec- tion, FDA shall waive the requirement for the submission of evidence of
p.000192: in vivo bioavailability or bioequivalence if the drug product meets any of the provisions of paragraphs (b),
p.000192: (c), (d), or
p.000192: (e) of this section.
p.000192: (b) For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be
p.000192: self-evi- dent. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the
p.000192: bioavailability or demonstrating the bioequivalence of these drug products. A drug product’s in vivo
p.000192: bioavailability or bioequiva- lence may be considered self-evident based on other data in the
p.000192: application if the product meets one of the fol- lowing criteria:
p.000192: (1) The drug product:
p.000192: (i) Is a parenteral solution intended solely for administration by injection, or an ophthalmic or otic
p.000192: solution; and
p.000192: (ii) Contains the same active and in- active ingredients in the same con- centration as a drug product
p.000192: that is the subject of an approved full new drug application or abbreviated new drug application.
p.000192: (2) The drug product:
p.000192: (i) Is administered by inhalation as a gas, e.g., a medicinal or an inhalation anesthetic; and
p.000192: (ii) Contains an active ingredient in the same dosage form as a drug product that is the subject of an
p.000192: approved full new drug application or abbreviated new drug application.
p.000192: (3) The drug product:
p.000192: (i) Is a solution for application to the skin, an oral solution, elixir, syrup, tincture, a solution for
p.000192: aerosolization
p.000192:
p.000192: or nebulization, a nasal solution, or similar other solubilized form; and
p.000192: (ii) Contains an active drug ingre- dient in the same concentration and dosage form as a drug
p.000192: product that is the subject of an approved full new drug application or abbreviated new drug
p.000192: application; and
p.000192: (iii) Contains no inactive ingredient or other change in formulation from the drug product that is the
p.000192: subject of the approved full new drug application or abbreviated new drug application that may
p.000192: significantly affect absorp- tion of the active drug ingredient or active moiety for products that
p.000192: are systemically absorbed, or that may sig- nificantly affect systemic or local availability for
p.000192: products intended to act locally.
p.000192: (c) FDA shall waive the requirement for the submission of evidence meas- uring the in vivo
p.000192: bioavailability or demonstrating the in vivo bioequiva- lence of a solid oral dosage form (other than a delayed
p.000192: release or extended re- lease dosage form) of a drug product determined to be effective for at least
p.000192: one indication in a Drug Efficacy Study Implementation notice or which is identical, related, or
p.000192: similar to such a drug product under § 310.6 of this chapter unless FDA has evaluated the drug
p.000192: product under the criteria set forth in § 320.33, included the drug prod- uct in the Approved Drug
p.000192: Products with Therapeutic Equivalence Evalua- tions List, and rated the drug product as having a known
p.000192: or potential bio- equivalence problem. A drug product so rated reflects a determination by FDA that an in vivo
p.000192: bioequivalence study is required.
p.000192: (d) For certain drug products, bio-
p.000192: availability may be measured or bio- equivalence may be demonstrated by evidence obtained in vitro in
p.000192: lieu of in vivo data. FDA shall waive the require- ment for the submission of evidence obtained in vivo
p.000192: measuring the bio- availability or demonstrating the bio- equivalence of the drug product if the drug
p.000192: product meets one of the fol- lowing criteria:
p.000192: (1) [Reserved]
p.000192: (2) The drug product is in the same dosage form, but in a different strength, and is
p.000192: proportionally similar in its active and inactive ingredients to
p.000193: 193
p.000193:
p.000193:
p.000193:
p.000193:
p.000193:
p.000193:
p.000193:
p.000193:
p.000193: § 320.23
p.000193: another drug product for which the same manufacturer has obtained ap- proval and the conditions
p.000193: in para- graphs (d)(2)(i) through (d)(2)(iii) of this section are met:
p.000193: (i) The bioavailability of this other drug product has been measured;
p.000193: (ii) Both drug products meet an ap- propriate in vitro test approved by FDA; and
p.000193: (iii) The applicant submits evidence showing that both drug products are proportionally similar in their
p.000193: active and inactive ingredients.
p.000193: (iv) Paragraph (d) of this section does not apply to delayed release or ex- tended release products.
p.000193: (3) The drug product is, on the basis of scientific evidence submitted in the application, shown to meet
p.000193: an in vitro test that has been correlated with in vivo data.
p.000193: (4) The drug product is a reformu- lated product that is identical, except for a different color, flavor, or
p.000193: preserv- ative that could not affect the bio- availability of the reformulated prod- uct, to another
p.000193: drug product for which the same manufacturer has obtained approval and the following conditions are met:
p.000193: (i) The bioavailability of the other product has been measured; and
p.000193: (ii) Both drug products meet an ap- propriate in vitro test approved by FDA.
p.000193: (e) FDA, for good cause, may waive a requirement for the submission of evi- dence of in vivo bioavailability
p.000193: or bio- equivalence if waiver is compatible with the protection of the public health. For
p.000193: full new drug applications, FDA may defer a requirement for the submission of evidence of in vivo bio-
p.000193: availability if deferral is compatible with the protection of the public health.
p.000193: (f) FDA, for good cause, may require evidence of in vivo bioavailability or bioequivalence for any drug
p.000193: product if the agency determines that any dif- ference between the drug product and a listed drug
p.000193: may affect the bio- availability or bioequivalence of the drug product.
p.000193: [57 FR 17998, Apr. 28, 1992, as amended at 67
p.000193: FR 77673, Dec. 19, 2002]
p.000193: 21 CFR Ch. I (4–1–12 Edition)
p.000193:
p.000193: § 320.23 Basis for measuring in vivo bioavailability or demonstrating bioequivalence.
p.000193: (a)(1) The in vivo bioavailability of a drug product is measured if the prod- uct’s rate and extent of
p.000193: absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug
p.000193: ingredient in the blood, urinary excretion rates, or pharma- cological effects, do not indicate a
p.000193: sig- nificant difference from the reference material’s rate and extent of absorp- tion. For drug products that
p.000193: are not in- tended to be absorbed into the blood- stream, bioavailability may be as- sessed by
p.000193: measurements intended to re- flect the rate and extent to which the active ingredient or active moiety be-
p.000193: comes available at the site of action.
p.000193: (2) Statistical techniques used shall be of sufficient sensitivity to detect differences in rate and
p.000193: extent of ab- sorption that are not attributable to subject variability.
p.000193: (3) A drug product that differs from the reference material in its rate of ab- sorption, but not in its
p.000193: extent of ab- sorption, may be considered to be bio- available if the difference in the rate of absorption
p.000193: is intentional, is appro- priately reflected in the labeling, is not essential to the attainment of effective
p.000193: body drug concentrations on chronic use, and is considered medically insig- nificant for the drug product.
p.000193: (b) Two drug products will be consid- ered bioequivalent drug products if they are pharmaceutical equivalents
p.000193: or pharmaceutical alternatives whose rate and extent of absorption do not show a significant
p.000193: difference when ad- ministered at the same molar dose of the active moiety under similar experi- mental
p.000193: conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alter-
p.000193: natives may be equivalent in the ex- tent of their absorption but not in their rate of absorption and
p.000193: yet may be considered bioequivalent because such differences in the rate of absorption are
p.000193:
p.000194: 194
p.000194:
p.000194:
p.000194:
p.000194:
p.000194:
p.000194:
p.000194:
p.000194: Food and Drug Administration, HHS § 320.24
p.000194:
p.000194:
p.000194: intentional and are reflected in the la- beling, are not essential to the attain- ment of effective body
p.000194: drug concentra- tions on chronic use, and are consid- ered medically insignificant for the particular
p.000194: drug product studied.
p.000194: [57 FR 17999, Apr. 28, 1992, as amended at 67
p.000194: FR 77673, Dec. 19, 2002]
p.000194:
p.000194: § 320.24 Types of evidence to measure bioavailability or establish bio- equivalence.
p.000194: (a) Bioavailability may be measured or bioequivalence may be dem- onstrated by several in
p.000194: vivo and in vitro methods. FDA may require in vivo or in vitro testing, or both, to measure
p.000194: the bioavailability of a drug product or establish the bioequivalence of specific drug products. Information
p.000194: on bioequivalence requirements for specific products is included in the cur- rent edition of FDA’s publication
p.000194: ‘‘Ap- proved Drug Products with Thera- peutic Equivalence Evaluations’’ and any current supplement to
p.000194: the publica- tion. The selection of the method used to meet an in vivo or in vitro testing requirement
p.000194: depends upon the purpose of the study, the analytical methods available, and the nature of the drug
p.000194: product. Applicants shall conduct bio- availability and bioequivalence testing using the most accurate,
p.000194: sensitive, and reproducible approach available among those set forth in paragraph (b) of this section. The
p.000194: method used must be ca- pable of measuring bioavailability or establishing bioequivalence, as appro- priate,
p.000194: for the product being tested.
p.000194: (b) The following in vivo and in vitro approaches, in descending order of ac- curacy, sensitivity, and
p.000194: reproduc- ibility, are acceptable for determining the bioavailability or bioequivalence of a drug product.
p.000194: (1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety,
p.000194: and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological
p.000194: fluid is meas- ured as a function of time. This ap- proach is particularly applicable to dosage
p.000194: forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body;
p.000194: or
p.000194:
p.000194: (ii) An in vitro test that has been correlated with and is predictive of human in vivo
p.000194: bioavailability data; or
p.000194: (2) An in vivo test in humans in which the urinary excretion of the ac- tive moiety, and, when
p.000194: appropriate, its active metabolite(s), are measured as a function of time. The intervals at which
p.000194: measurements are taken should ordinarily be as short as possible so that the measure of the rate of
p.000194: elimi- nation is as accurate as possible. De- pending on the nature of the drug prod- uct, this approach may be
p.000194: applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section. This
p.000194: method is not appropriate where urinary excretion is not a significant mechanism of elimination.
p.000194: (3) An in vivo test in humans in
p.000194: which an appropriate acute pharma- cological effect of the active moiety, and, when appropriate, its
p.000194: active me- tabolite(s), are measured as a function of time if such effect can be measured with
p.000194: sufficient accuracy, sensitivity, and reproducibility. This approach is applicable to the category of
p.000194: dosage forms described in paragraph (b)(1)(i) of this section only when appropriate methods are not
p.000194: available for measure- ment of the concentration of the moi- ety, and, when appropriate, its active
p.000194: metabolite(s), in biological fluids or ex- cretory products but a method is avail- able for the measurement of an
p.000194: appro- priate acute pharmacological effect. This approach may be particularly ap- plicable to dosage
p.000194: forms that are not intended to deliver the active moiety to the bloodstream for systemic dis-
p.000194: tribution.
p.000194: (4) Well-controlled clinical trials that
p.000194: establish the safety and effectiveness of the drug product, for purposes of measuring
p.000194: bioavailability, or appro- priately designed comparative clinical trials, for purposes of demonstrating
p.000194: bioequivalence. This approach is the least accurate, sensitive, and reproduc- ible of the general
p.000194: approaches for measuring bioavailability or dem- onstrating bioequivalence. For dosage forms
p.000194: intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be con-
p.000194: sidered acceptable only when analyt- ical methods cannot be developed to permit use of one of
p.000194: the approaches
p.000195: 195
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195: § 320.25
p.000195: outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the ap- proaches described
p.000195: in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of this section are not available. This ap-
p.000195: proach may also be considered suffi- ciently accurate for measuring bio- availability or
p.000195: demonstrating bio- equivalence of dosage forms intended to deliver the active moiety locally, e.g.,
p.000195: topical preparations for the skin, eye, and mucous membranes; oral dos- age forms not intended to be
p.000195: absorbed, e.g., an antacid or radiopaque medium; and bronchodilators administered by inhalation if the onset
p.000195: and duration of pharmacological activity are defined.
p.000195: (5) A currently available in vitro test
p.000195: acceptable to FDA (usually a dissolu- tion rate test) that ensures human in vivo bioavailability.
...
p.000195: intended to be used interchangeably; or
p.000195: (3) Has greater than anticipated po- tential toxicity related to pharmaco- kinetic or other characteristics.
p.000195: [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July
p.000195: 1, 1992, as amended at 67 FR 77673, Dec. 19,
p.000195: 2002]
p.000195:
p.000195: § 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000195: (a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no
p.000195: unnecessary human re- search should be done.
p.000195: (2) An in vivo bioavailability study is generally done in a normal adult popu- lation under standardized
p.000195: conditions. In some situations, an in vivo bio- availability study in humans may pref- erably and more
p.000195: properly be done in suitable patients. Critically ill patients
p.000195: 21 CFR Ch. I (4–1–12 Edition)
p.000195: shall not be included in an in vivo bio- availability study unless the attending physician determines that there
p.000195: is a potential benefit to the patient.
p.000195: (b) Basic design. The basic design of an in vivo bioavailability study is de- termined by the following:
p.000195: (1) The scientific questions to be an- swered.
p.000195: (2) The nature of the reference mate- rial and the dosage form to be tested.
p.000195: (3) The availability of analytical methods.
p.000195: (4) Benefit-risk considerations in re- gard to testing in humans.
p.000195: (c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in
p.000195: comparison to an appropriate reference material unless some other approach is more appro- priate for
p.000195: valid scientific reasons.
p.000195: (d) Previously unmarketed active drug ingredients or therapeutic moieties. (1) An in vivo bioavailability
p.000195: study involving a drug product containing an active drug ingredient or therapeutic moiety that has not
p.000195: been approved for mar- keting can be used to measure the fol- lowing pharmacokinetic data:
p.000195: (i) The bioavailability of the formu- lation proposed for marketing; and
p.000195: (ii) The essential pharmacokinetic characteristics of the active drug in- gredient or therapeutic moiety,
p.000195: such as the rate of absorption, the extent of ab- sorption, the half-life of the thera- peutic moiety in
p.000195: vivo, and the rate of excretion and/or metabolism. Dose pro- portionality of the active drug ingre- dient or
p.000195: the therapeutic moiety needs to be established after single-dose ad- ministration and in certain instances
p.000195: after multiple-dose administration. This characterization is a necessary part of the investigation of
p.000195: the drug to support drug labeling.
p.000195: (2) The reference material in such a bioavailability study should be a solu- tion or suspension containing
p.000195: the same quantity of the active drug ingredient or therapeutic moiety as the formula- tion proposed for
p.000195: marketing.
p.000195: (3) The reference material should be administered by the same route as the formulation proposed for
p.000195: marketing unless an alternative or additional
p.000196: 196
p.000196:
p.000196:
p.000196:
p.000196:
p.000196:
p.000196:
p.000196:
p.000196: Food and Drug Administration, HHS § 320.25
p.000196:
p.000196:
p.000196: route is necessary to answer the sci- entific question under study. For ex- ample, in the case of an active
p.000196: drug in- gredient or therapeutic moiety that is poorly absorbed after oral administra- tion, it may be
p.000196: necessary to compare the oral dosage form proposed for mar- keting with the active drug ingredient or
p.000196: therapeutic moiety administered in solution both orally and intravenously.
p.000196: (e) Ne formulations of active drug in- gredients or therapeutic moieties approved for marketing. (1) An
p.000196: in vivo bio- availability study involving a drug product that is a new dosage form, or a new salt or
p.000196: ester of an active drug in- gredient or therapeutic moiety that has been approved for marketing can
p.000196: be used to:
p.000196: (i) Measure the bioavailability of the new formulation, new dosage form, or new salt or ester relative to an
p.000196: appro- priate reference material; and
p.000196: (ii) Define the pharmacokinetic pa- rameters of the new formulation, new dosage form, or new salt or ester to
p.000196: es- tablish dosage recommendation.
p.000196: (2) The selection of the reference ma- terial(s) in such a bioavailability study depends upon the scientific
p.000196: questions to be answered, the data needed to es- tablish comparability to a currently marketed drug
p.000196: product, and the data needed to establish dosage rec- ommendations.
p.000196: (3) The reference material should be taken from a current batch of a drug product that is the subject
p.000196: of an ap- proved new drug application and that contains the same active drug ingre- dient or therapeutic
p.000196: moiety, if the new formulation, new dosage form, or new salt or ester is intended to be com- parable
p.000196: to or to meet any comparative labeling claims made in relation to the drug product that is the subject of
p.000196: an approved new drug application.
p.000196: (f) Extended release formulations. (1) The purpose of an in vivo bio- availability study
p.000196: involving a drug product for which an extended release claim is made is to determine if all of the
p.000196: following conditions are met:
p.000196: (i) The drug product meets the ex- tended release claims made for it.
p.000196: (ii) The bioavailability profile estab- lished for the drug product rules out the occurrence of any dose
p.000196: dumping.
p.000196:
p.000196: (iii) The drug product’s steady-state performance is equivalent to a cur- rently marketed nonextended
p.000196: release or extended release drug product that contains the same active drug ingre- dient or therapeutic
p.000196: moiety and that is subject to an approved full new drug application.
p.000196: (iv) The drug product’s formulation provides consistent pharmacokinetic performance between individual dosage
p.000196: units.
p.000196: (2) The reference material(s) for such a bioavailability study shall be chosen to permit an appropriate
p.000196: scientific evaluation of the extended release claims made for the drug product. The reference
p.000196: material shall be one of the following or any combination thereof:
p.000196: (i) A solution or suspension of the ac- tive drug ingredient or therapeutic moiety.
p.000196: (ii) A currently marketed noncon- trolled release drug product containing the same active drug
p.000196: ingredient or therapeutic moiety and administered according to the dosage recommenda- tions in the
p.000196: labeling of the noncon- trolled release drug product.
p.000196: (iii) A currently marketed extended release drug product subject to an ap- proved full new drug
p.000196: application con- taining the same active drug ingre- dient or therapeutic moiety and admin- istered
p.000196: according to the dosage rec- ommendations in the labeling proposed for the extended release drug product.
p.000196: (iv) A reference material other than one set forth in paragraph (f)(2) (i), (ii) or (iii) of this section
p.000196: that is appro- priate for valid scientific reasons.
p.000196: (g) Combination drug products. (1) Gen- erally, the purpose of an in vivo bio- availability study involving a
p.000196: combina- tion drug product is to determine if the rate and extent of absorption of each active drug ingredient
p.000196: or therapeutic moiety in the combination drug prod- uct is equivalent to the rate and extent of absorption of
p.000196: each active drug ingre- dient or therapeutic moiety adminis- tered concurrently in separate single- ingredient
p.000196: preparations.
p.000196: (2) The reference material in such a bioavailability study should be two or more currently marketed,
p.000196: single-ingre- dient drug products each of which con- tains one of the active drug ingredients
p.000197: 197
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197: § 320.26
p.000197: or therapeutic moieties in the com- bination drug product. The Food and Drug Administration may,
p.000197: for valid scientific reasons, specify that the ref- erence material shall be a combination drug product that
p.000197: is the subject of an approved new drug application.
p.000197: (3) The Food and Drug Administra- tion may permit a bioavailability study involving a
p.000197: combination drug product to determine the rate and ex- tent of absorption of selected, but not all,
p.000197: active drug ingredients or thera- peutic moieties in the combination drug product. The Food and Drug
p.000197: Ad- ministration may permit this deter- mination if the pharmacokinetics and the interactions of the
p.000197: active drug in- gredients or therapeutic moieties in the combination drug product are well known and
p.000197: the therapeutic activity of the combination drug product is gen- erally recognized to reside in only one
p.000197: of the active drug ingredients or thera- peutic moieties, e.g., ampicillin in an ampicillin-probenecid
p.000197: combination drug product.
p.000197: (h) Use of a placebo as the reference material. Where appropriate or where necessary to
p.000197: demonstrate the sensi- tivity of the test, the reference mate- rial in a bioavailability study may be a
p.000197: placebo if:
p.000197: (1) The study measures the thera- peutic or acute pharmacological effect of the active drug
p.000197: ingredient or thera- peutic moiety; or
p.000197: (2) The study is a clinical trial to es- tablish the safety and effectiveness of the drug product.
p.000197: (i) Standards for test drug product and reference material. (1) Both the drug product to be tested
p.000197: and the reference material, if it is another drug product, shall be shown to meet all compendial or
p.000197: other applicable standards of iden- tity, strength, quality, and purity, in- cluding potency and, where
p.000197: applicable, content uniformity, disintegration times, and dissolution rates.
p.000197: (2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same
p.000197: conditions as those used for full-scale production.
p.000197: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000197: 77674, Dec. 19, 2002]
p.000197: 21 CFR Ch. I (4–1–12 Edition)
p.000197:
p.000197: § 320.26 Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.
p.000197: (a) Basic principles. (1) An in vivo bio- availability or bioequivalence study should be a single-dose
p.000197: comparison of the drug product to be tested and the appropriate reference material con- ducted in
p.000197: normal adults.
p.000197: (2) The test product and the reference material should be administered to subjects in the fasting
p.000197: state, unless some other approach is more appro- priate for valid scientific reasons.
p.000197: (b) Study design. (1) A single-dose study should be crossover in design, unless a parallel design
p.000197: or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination
p.000197: period.
p.000197: (2) Unless some other approach is ap- propriate for valid scientific reasons, the drug elimination period
p.000197: should be either:
p.000197: (i) At least three times the half-life of the active drug ingredient or thera- peutic moiety, or its
p.000197: metabolite(s), measured in the blood or urine; or
p.000197: (ii) At least three times the half-life of decay of the acute pharmacological effect.
p.000197: (c) Collection of blood samples. (1) When comparison of the test product and the reference
p.000197: material is to be based on blood concentration time curves, unless some other approach is more
p.000197: appropriate for valid scientific reasons, blood samples should be taken with sufficient frequency to permit
p.000197: an estimate of both:
p.000197: (i) The peak concentration in the
p.000197: blood of the active drug ingredient or therapeutic moiety, or its metabo- lite(s), measured; and
p.000197: (ii) The total area under the curve for a time period at least three times the half-life of the active drug
p.000197: ingredient or therapeutic moiety, or its metabo- lite(s), measured.
p.000197: (2) In a study comparing oral dosage forms, the sampling times should be identical.
p.000197: (3) In a study comparing an intra- venous dosage form and an oral dosage form, the sampling times
p.000197: should be those needed to describe both:
p.000197: (i) The distribution and elimination phase of the intravenous dosage form; and
p.000198: 198
p.000198:
p.000198:
p.000198:
p.000198:
p.000198:
p.000198:
p.000198:
p.000198: Food and Drug Administration, HHS § 320.27
p.000198:
p.000198:
p.000198: (ii) The absorption and elimination phase of the oral dosage form.
p.000198: (4) In a study comparing drug deliv- ery systems other than oral or intra- venous dosage forms with
p.000198: an appro- priate reference standard, the sampling times should be based on valid sci- entific reasons.
p.000198: (d) Collection of urine samples. When comparison of the test product and the reference material is to be based
p.000198: on cu- mulative urinary excretion-time curves, unless some other approach is more appropriate
p.000198: for valid scientific reasons, samples of the urine should be collected with sufficient frequency to permit an
p.000198: estimate of the rate and ex- tent of urinary excretion of the active drug ingredient or therapeutic
p.000198: moiety, or its metabolite(s), measured.
p.000198: (e) Measurement of an acute pharma-
p.000198: cological effect. (1) When comparison of the test product and the reference ma- terial is to be based
p.000198: on acute pharma- cological effect-time curves, measure- ments of this effect should be made with
p.000198: sufficient frequency to permit a reasonable estimate of the total area under the curve for a time period
p.000198: at least three times the half-life of decay of the pharmacological effect, unless some other
p.000198: approach is more appro- priate for valid scientific reasons.
p.000198: (2) The use of an acute pharma-
p.000198: cological effect to determine bio- availability may further require dem- onstration of dose-related
p.000198: response. In such a case, bioavailability may be de- termined by comparison of the dose-re- sponse curves as
p.000198: well as the total area under the acute pharmacological ef- fect-time curves for any given dose.
p.000198: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000198: 77674, Dec. 19, 2002]
p.000198:
p.000198: § 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study.
p.000198: (a) Basic principles. (1) In selected cir- cumstances it may be necessary for the test product and the reference
p.000198: material to be compared after repeated adminis- tration to determine steady-state lev- els of the active
p.000198: drug ingredient or therapeutic moiety in the body.
p.000198: (2) The test product and the reference
p.000198: material should be administered to subjects in the fasting or nonfasting state, depending upon the
p.000198: conditions
p.000198:
p.000198: reflected in the proposed labeling of the test product.
p.000198: (3) A multiple-dose study may be re- quired to determine the bioavailability of a drug product in the
p.000198: following cir- cumstances:
p.000198: (i) There is a difference in the rate of absorption but not in the extent of ab- sorption.
p.000198: (ii) There is excessive variability in bioavailability from subject to subject.
p.000198: (iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the
p.000198: blood re- sulting from a single dose is too low for accurate determination by the analyt- ical method.
p.000198: (iv) The drug product is an extended release dosage form.
p.000198: (b) Study design. (1) A multiple-dose study should be crossover in design, unless a parallel design or
p.000198: other design is more appropriate for valid scientific reasons, and should provide for a drug elimination
p.000198: period if steady-state con- ditions are not achieved.
p.000198: (2) A multiple-dose study is not re- quired to be of crossover design if the study is to establish
p.000198: dose proportion- ality under a multiple-dose regimen or to establish the pharmacokinetic pro- file of a
p.000198: new drug product, a new drug delivery system, or an extended release dosage form.
p.000198: (3) If a drug elimination period is re- quired, unless some other approach is more appropriate for
p.000198: valid scientific reasons, the drug elimination period should be either:
p.000198: (i) At least five times the half-life of the active drug ingredient or thera- peutic moiety, or
p.000198: its active metabo- lite(s), measured in the blood or urine; or
p.000198: (ii) At least five times the half-life of decay of the acute pharmacological ef- fect.
p.000198: (c) Achievement of steady-state condi- tions. Whenever a multiple-dose study is conducted, unless some
p.000198: other ap- proach is more appropriate for valid scientific reasons, sufficient doses of the test
p.000198: product and reference material should be administered in accordance with the labeling to achieve steady-
p.000198: state conditions.
p.000198: (d) Collection of blood or urine samples.
p.000198: (1) Whenever comparison of the test product and the reference material is
p.000199: 199
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199: § 320.28
p.000199: to be based on blood concentration- time curves at steady state, appro- priate dosage
p.000199: administration and sam- pling should be carried out to docu- ment attainment of steady state.
p.000199: (2) Whenever comparison of the test product and the reference material is to be based on cumulative
p.000199: urinary ex- cretion-time curves at steady state, ap- propriate dosage administration and sampling should be
p.000199: carried out to docu- ment attainment of steady state.
p.000199: (3) A more complete characterization of the blood concentration or urinary excretion rate during the
p.000199: absorption and elimination phases of a single dose administered at steady-state is encour- aged to permit estimation
p.000199: of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain
p.000199: pharmacokinetic information, e.g., half-life or blood clearance, that is essential in pre-
p.000199: paring adequate labeling for the drug product.
p.000199: (e) Steady-state parameters. (1) In cer- tain instances, e.g., in a study involv- ing a new drug entity,
p.000199: blood clearances at steady-state obtained in a multiple-
p.000199: dose study should be compared to blood clearances obtained in a single-dose study to support adequate
p.000199: dosage rec- ommendations.
p.000199: (2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a
p.000199: multiple- dose steady-state study is directly pro- portional to the fraction of the dose ab- sorbed and is
p.000199: equal to the cor- responding ‘‘zero to infinity’’ area under the curve for a single-dose study.
p.000199: Therefore, when steady-state condi- tions are achieved, a comparison of blood concentrations
p.000199: during a dosing interval may be used to define the frac- tion of the active drug ingredient or therapeutic
p.000199: moiety absorbed.
p.000199: (3) Other methods based on valid sci-
p.000199: entific reasons should be used to deter- mine the bioavailability of a drug prod- uct having dose-dependent
p.000199: kinetics (non-linear system).
p.000199: (f) Measurement of an acute pharma- cological effect. When comparison of the test product and the reference
p.000199: material is to be based on acute pharma- cological effect-time curves, measure- ments of this
p.000199: effect should be made with sufficient frequency to dem-
p.000199: 21 CFR Ch. I (4–1–12 Edition)
p.000199: onstrate a maximum effect and a lack of significant difference between the test product and the
p.000199: reference mate- rial.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.28 Correlation of bioavailability with an acute pharmacological ef- fect or clinical evidence.
p.000199: Correlation of in vivo bioavailability data with an acute pharmacological ef- fect or clinical evidence of
p.000199: safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g.,
p.000199: in the case of an extended release preparation.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.29 Analytical methods for an in vivo bioavailability or bioequiva- lence study.
p.000199: (a) The analytical method used in an in vivo bioavailability or bioequiva- lence study to measure the
p.000199: concentra- tion of the active drug ingredient or therapeutic moiety, or its active me- tabolite(s), in
p.000199: body fluids or excretory products, or the method used to meas- ure an acute pharmacological effect
p.000199: shall be demonstrated to be accurate and of sufficient sensitivity to meas- ure, with appropriate precision,
p.000199: the ac- tual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s),
p.000199: achieved in the body.
p.000199: (b) When the analytical method is not sensitive enough to measure accu- rately the concentration of
p.000199: the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or
p.000199: excretory products produced by a single dose of the test product, two or more single doses may be given
p.000199: together to produce higher concentra- tion if the requirements of § 320.31 are met.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.30 Inquiries regarding bio- availability and bioequivalence re- quirements and review of
p.000199: protocols by the Food and Drug Administra- tion.
p.000199: (a) The Commissioner of Food and Drugs strongly recommends that, to
p.000200: 200
p.000200:
p.000200:
p.000200:
p.000200:
p.000200:
p.000200:
p.000200:
p.000200: Food and Drug Administration, HHS § 320.31
p.000200:
p.000200:
p.000200: avoid the conduct of an improper study and unnecessary human research, any person planning to conduct a
p.000200: bio- availability or bioequivalence study submit the proposed protocol for the study to FDA for
p.000200: review prior to the initiation of the study.
p.000200: (b) FDA may review a proposed pro- tocol for a bioavailability or bioequiva- lence study and will offer
p.000200: advice with respect to whether the following condi- tions are met:
p.000200: (1) The design of the proposed bio- availability or bioequivalence study is appropriate.
p.000200: (2) The reference material to be used in the bioavailability or bioequivalence study is appropriate.
p.000200: (3) The proposed chemical and statis- tical analytical methods are adequate. (c)(1) General inquiries relating
p.000200: to in vivo bioavailability requirements and methodology shall be submitted to the Food and Drug
p.000200: Administration, Center for Drug Evaluation and Research, Of- fice of Clinical Pharmacology, 10903 New
p.000200: Hampshire Ave., Silver Spring,
p.000200: MD 20993–0002.
p.000200: (2) General inquiries relating to bio- equivalence requirements and method- ology shall be submitted to
p.000200: the Food and Drug Administration, Center for Drug Evaluation and Research, Divi- sion of
p.000200: Bioequivalence (HFD–650), 7500 Standish Pl., Rockville, MD 20855–2773.
p.000200: [57 FR 18000, Apr. 28, 1992, as amended at 67
p.000200: FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26,
p.000200: 2009]
p.000200:
p.000200: § 320.31 Applicability of requirements regarding an ‘‘Investigational New Drug Application.’’
p.000200: (a) Any person planning to conduct an in vivo bioavailability or bioequiva- lence study in humans shall
p.000200: submit an ‘‘Investigational New Drug Applica- tion’’ (IND) if:
p.000200: (1) The test product contains a new chemical entity as defined in
p.000200: § 314.108(a) of this chapter; or
p.000200: (2) The study involves a radioactively labeled drug product; or
p.000200: (3) The study involves a cytotoxic drug product.
p.000200: (b) Any person planning to conduct a bioavailability or bioequivalence study in humans using a drug product that
p.000200: contains an already approved, non-new
p.000200:
p.000200: chemical entity shall submit an IND if the study is one of the following:
p.000200: (1) A single-dose study in normal sub- jects or patients where either the max- imum single or total daily dose exceeds
p.000200: that specified in the labeling of the drug product that is the subject of an approved new drug
p.000200: application or ab- breviated new drug application.
p.000200: (2) A multiple-dose study in normal subjects or patients where either the single or total daily dose
p.000200: exceeds that specified in the labeling of the drug product that is the subject of an ap- proved
p.000200: new drug application or abbre- viated new drug application.
p.000200: (3) A multiple-dose study on an ex- tended release product on which no sin- gle-dose study has been completed.
p.000200: (c) The provisions of parts 50, 56, and
p.000200: 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans
p.000200: conducted under an IND.
p.000200: (d) A bioavailability or bioequiva- lence study in humans other than one described in paragraphs (a)
p.000200: through (c) of this section is exempt from the re- quirements of part 312 of this chapter if the following
p.000200: conditions are satisfied:
p.000200: (1) If the study is one described under
p.000200: § 320.38(b) or § 320.63, the person con- ducting the study, including any con- tract research
p.000200: organization, must re- tain reserve samples of any test article and reference standard used in the study
p.000200: and release the reserve samples to FDA upon request, in accordance with, and for the period
p.000200: specified in,
p.000200: § 320.38;
p.000200: (2) An in vivo bioavailability or bio- equivalence study in humans must be conducted in compliance with
p.000200: the re- quirements for institutional review set forth in part 56 of this chapter, and in- formed consent set forth
p.000200: in part 50 of this chapter; and
p.000200: (3) The person conducting the study, including any contract research orga- nization, must notify FDA and
p.000200: all par- ticipating investigators of any serious adverse event, as defined in § 312.32(a), observed during
p.000200: the conduct of the study as soon as possible but in no case later than 15 calendar days after be- coming
p.000200: aware of its occurrence. Each report must be submitted on FDA Form 3500A or in an electronic format
p.000201: 201
p.000201:
p.000201:
p.000201:
p.000201:
p.000201:
p.000201:
p.000201:
p.000201:
p.000201: § 320.32
p.000201: that FDA can process, review, and ar- chive. FDA will periodically issue guid- ance on how to provide the
p.000201: electronic submission (e.g., method of trans- mission, media, file formats, prepara- tion and
p.000201: organization of files). Each re- port must bear prominent identifica- tion of its contents, i.e.,
p.000201: ‘‘bio- availability/bioequivalence safety re- port.’’ The person conducting the study, including
p.000201: any contract research organization, must also notify FDA of any fatal or life-threatening adverse event
p.000201: from the study as soon as pos- sible but in no case later than 7 cal- endar days after becoming aware of
p.000201: its occurrence. Each notification under this paragraph must be submitted to the Director, Office of
p.000201: Generic Drugs in the Center for Drug Evaluation and Re- search at FDA. Relevant followup in- formation to
p.000201: a bioavailability/bio- equivalence safety report must be sub- mitted as soon as the information is
p.000201: available and must be identified as such, i.e., ‘‘Followup bioavailability/ bioequivalence safety
p.000201: report.’’ Upon re- quest from FDA, the person conducting the study, including any contract re- search
p.000201: organization, must submit to FDA any additional data or informa- tion that the agency deems necessary,
p.000201: as soon as possible, but in no case later than 15 calendar days after receiving the request.
p.000201: [57 FR 18000, Apr. 28, 1992, as amended at 58
p.000201: FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19,
p.000201: 2002; 75 FR 59963, Sept. 29, 2010]
p.000201:
p.000201: § 320.32 Procedures for establishing or amending a bioequivalence require- ment.
p.000201: (a) The Food and Drug Administra- tion, on its own initiative or in re- sponse to a petition by
p.000201: an interested person, may propose and promulgate a regulation to establish a bioequiva- lence
p.000201: requirement for a product not subject to section 505(j) of the act if it finds there is
p.000201: well-documented evi- dence that specific pharmaceutical equivalents or pharmaceutical alter- natives
p.000201: intended to be used inter- changeably for the same therapeutic effect:
p.000201: (1) Are not bioequivalent drug prod- ucts; or
p.000201: 21 CFR Ch. I (4–1–12 Edition)
p.000201: (2) May not be bioequivalent drug products based on the criteria set forth in § 320.33; or
p.000201: (3) May not be bioequivalent drug products because they are members of a class of drug products that
p.000201: have close structural similarity and similar phys- icochemical or pharmacokinetic prop- erties to other drug
p.000201: products in the same class that FDA finds are not bio- equivalent drug products.
p.000201: (b) FDA shall include in a proposed rule to establish a bioequivalence re- quirement the evidence and
p.000201: criteria set forth in § 320.33 that are to be consid- ered in determining whether to issue the proposal.
p.000201: If the rulemaking is pro- posed in response to a petition, FDA shall include in the proposal a sum-
p.000201: mary and analysis of the relevant in- formation that was submitted in the petition as well as other
p.000201: available in- formation to support the establishment of a bioequivalence requirement.
p.000201: (c) FDA, on its own initiative or in response to a petition by an interested person, may propose and
p.000201: promulgate an amendment to a bioequivalence re- quirement established under this sub- part.
p.000201: [57 FR 18000, Apr. 28, 1992]
p.000201:
p.000201: § 320.33 Criteria and evidence to as- sess actual or potential bioequiva- lence problems.
p.000201: The Commissioner of Food and Drugs shall consider the following factors, when supported by
p.000201: well-documented evidence, to identify specific pharma- ceutical equivalents and pharma- ceutical
p.000201: alternatives that are not or may not be bioequivalent drug prod- ucts.
p.000201: (a) Evidence from well-controlled clinical trials or controlled observa- tions in patients that
p.000201: such drug prod- ucts do not give comparable thera- peutic effects.
p.000201: (b) Evidence from well-controlled bioequivalence studies that such prod- ucts are not bioequivalent
p.000201: drug prod- ucts.
p.000201: (c) Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than
p.000201: a 2-fold dif- ference in median lethal dose (LD50)
p.000202: 202
p.000202:
p.000202:
p.000202:
p.000202:
p.000202:
p.000202:
p.000202:
p.000202: Food and Drug Administration, HHS § 320.34
p.000202:
p.000202:
p.000202: and median effective dose (ED50) val- ues, or have less than a 2-fold dif- ference in the
p.000202: minimum toxic con- centrations and minimum effective concentrations in the blood, and safe and
p.000202: effective use of the drug products requires careful dosage titration and patient monitoring.
p.000202: (d) Competent medical determination that a lack of bioequivalence would have a serious adverse effect
p.000202: in the treatment or prevention of a serious disease or condition.
p.000202: (e) Physicochemical evidence that:
p.000202: (1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter,
p.000202: or, if dis- solution in the stomach is critical to absorption, the volume of gastric fluids required to
p.000202: dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100
p.000202: milliliters for adults and prorated for infants and children).
p.000202: (2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in
p.000202: 30 minutes when tested using either a general method specified in an official compendium or a paddle
p.000202: method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37 C, or
p.000202: differs sig- nificantly from that of an appropriate reference material such as an identical drug product that
p.000202: is the subject of an approved full new drug application.
p.000202: (3) The particle size and/or surface area of the active drug ingredient is critical in
p.000202: determining its bio- availability.
p.000202: (4) Certain physical structural char- acteristics of the active drug ingre- dient, e.g., polymorphic
p.000202: forms, con- forms, solvates, complexes, and crystal modifications, dissolve poorly and this poor dissolution may
p.000202: affect absorption.
p.000202: (5) Such drug products have a high ratio of excipients to active ingredi- ents, e.g., greater than 5 to
p.000202: 1.
p.000202: (6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic excipients and lubricants, either may be
p.000202: required for absorption of the active drug ingre- dient or therapeutic moiety or, alter- natively, if present,
p.000202: may interfere with such absorption.
p.000202: (f) Pharmacokinetic evidence that:
p.000202: (1) The active drug ingredient, thera- peutic moiety, or its precursor is ab-
p.000202:
p.000202: sorbed in large part in a particular seg- ment of the gastrointestinal tract or is absorbed from a localized site.
p.000202: (2) The degree of absorption of the ac- tive drug ingredient, therapeutic moi- ety, or its precursor is poor,
p.000202: e.g., less than 50 percent, ordinarily in compari- son to an intravenous dose, even when it is administered
p.000202: in pure form, e.g., in solution.
p.000202: (3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the
p.000202: process of ab- sorption (first-class metabolism) so the therapeutic effect and/or toxicity of such drug
p.000202: product is determined by the rate as well as the degree of absorp- tion.
p.000202: (4) The therapeutic moiety is rapidly
p.000202: metabolized or excreted so that rapid dissolution and absorption are required for effectiveness.
p.000202: (5) The active drug ingredient or therapeutic moiety is unstable in spe- cific portions of the
p.000202: gastrointestinal tract and requires special coatings or formulations, e.g., buffers, enteric coatings,
p.000202: and film coatings, to assure adequate absorption.
p.000202: (6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the
p.000202: rate and ex- tent of absorption are important to bioequivalence.
p.000202: [42 FR 1635, Jan. 7, 1977. Redesignated and
p.000202: amended at 57 FR 18001, Apr. 28, 1992]
p.000202:
p.000202: § 320.34 Requirements for batch test- ing and certification by the Food and Drug Administration.
p.000202: (a) If the Commissioner determines that individual batch testing by the Food and Drug Administration
p.000202: is nec- essary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall
p.000202: include in the bioequivalence requirement a require- ment for manufacturers to submit sam- ples of each
p.000202: batch to the Food and Drug Administration and to withhold distribution of the batch until notified by
p.000202: the Food and Drug Administration that the batch may be introduced into interstate commerce.
p.000202: (b) The Commissioner will ordinarily
p.000202: terminate a requirement for a manu- facturer to submit samples for batch testing on a finding that the
p.000202: manufac- turer has produced four consecutive
p.000203: 203
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203: § 320.35
p.000203: batches that were tested by the Food and Drug Administration and found to meet the bioequivalence
p.000203: requirement, unless the public health requires that batch testing be extended to additional batches.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992]
p.000203:
p.000203: § 320.35 Requirements for in vitro test- ing of each batch.
p.000203: If a bioequivalence requirement specifies a currently available in vitro test or an in
p.000203: vitro bioequivalence standard comparing the drug product to a reference standard, the manufac- turer shall
p.000203: conduct the test on a sam- ple of each batch of the drug product to assure batch-to-batch uniformity.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992]
p.000203:
p.000203: § 320.36 Requirements for mainte- nance of records of bioequivalence testing.
p.000203: (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure
p.000203: that the product meets a bioequivalence re- quirement shall be maintained by the manufacturer for at
p.000203: least 2 years after the expiration date of the batch and submitted to the Food and Drug Ad- ministration
p.000203: on request.
p.000203: (b) Any person who contracts with another party to conduct a bioequiva- lence study from which the data are
p.000203: in- tended to be submitted to FDA as part of an application submitted under part
p.000203: 314 of this chapter shall obtain from the person conducting the study suffi- cient accurate financial
p.000203: information to allow the submission of complete and accurate financial certifications or dis- closure statements
p.000203: required under part
p.000203: 54 of this chapter and shall maintain that information and all records relat- ing to the compensation
p.000203: given for that study and all other financial interest information required under part 54 of this chapter
p.000203: for 2 years after the date of approval of the application. The per- son maintaining these records shall,
p.000203: upon request for any properly author- ized officer or employee of the Food and Drug Administration, at
p.000203: reason- able time, permit such officer or em-
p.000203: 21 CFR Ch. I (4–1–12 Edition)
p.000203: ployee to have access to and copy and verify these records.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992, as amended at 63 FR
p.000203: 5252, Feb. 2, 1998]
p.000203:
p.000203: § 320.38 Retention of bioavailability samples.
p.000203: (a) The applicant of an application or supplemental application submitted under section 505 of the Federal
p.000203: Food, Drug, and Cosmetic Act, or, if bio- availability testing was performed under contract,
p.000203: the contract research organization shall retain an appro- priately identified reserve sample of the
p.000203: drug product for which the appli- cant is seeking approval (test article) and of the reference standard
p.000203: used to perform an in vivo bioavailability study in accordance with and for the studies described
p.000203: in paragraph (b) of this section that is representative of each sample of the test article and ref- erence
p.000203: standard provided by the appli- cant for the testing.
p.000203: (b) Reserve samples shall be retained for the following test articles and ref- erence standards and for the
p.000203: studies de- scribed:
p.000203: (1) If the formulation of the test arti- cle is the same as the formulation(s) used in the clinical
p.000203: studies dem- onstrating substantial evidence of safe- ty and effectiveness for the test arti- cle’s claimed
p.000203: indications, a reserve sample of the test article used to con- duct an in vivo bioavailability study
p.000203: comparing the test article to a ref- erence oral solution, suspension, or in- jection.
p.000203: (2) If the formulation of the test arti-
p.000203: cle differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety
p.000203: and ef- fectiveness for the test article’s claimed indications, a reserve sample of the test
p.000203: article and of the reference standard used to conduct an in vivo bioequivalence study comparing the
p.000203: test article to the formulation(s) (ref- erence standard) used in the clinical studies.
p.000203: (3) For a new formulation, new dos-
p.000203: age form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved
p.000203: for mar- keting, a reserve sample of the test ar- ticle and of the reference standard used
p.000204: 204
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204: Food and Drug Administration, HHS § 320.63
p.000204:
p.000204:
p.000204: to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference
p.000204: standard) that contains the same active drug in- gredient or therapeutic moiety.
p.000204: (c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of
p.000204: the release tests required in the application or supplemental application.
p.000204: (d) Each reserve sample shall be ade- quately identified so that the reserve sample can be positively
p.000204: identified as having come from the same sample as used in the specific bioavailability study.
p.000204: (e) Each reserve sample shall be stored under conditions consistent with product labeling and in
p.000204: an area segregated from the area where testing is conducted and with access limited to authorized personnel.
p.000204: Each reserve sample shall be retained for a period of at least 5 years following the date on which the
p.000204: application or supplemental application is approved, or, if such ap- plication or supplemental application
p.000204: is not approved, at least 5 years fol- lowing the date of completion of the bioavailability study in which
p.000204: the sam- ple from which the reserve sample was obtained was used.
p.000204: (f) Authorized FDA personnel will or- dinarily collect reserve samples di- rectly from the applicant or
p.000204: contract research organization at the storage site during a preapproval inspection. If authorized FDA
p.000204: personnel are unable to collect samples, FDA may require the applicant or contract research or- ganization
p.000204: to submit the reserve sam- ples to the place identified in the agen- cy’s request. If FDA has not collected
p.000204: or requested delivery of a reserve sam- ple, or if FDA has not collected or re- quested delivery of any
...
p.000204: from the same samples
p.000204:
p.000204: as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall
p.000204: be exe- cuted by an individual authorized to act for the applicant or contract re- search organization in
p.000204: releasing the re- serve samples to FDA.
p.000204: (h) A contract research organization may contract with an appropriate, independent third party
p.000204: to provide storage of reserve samples provided that the sponsor of the study has been notified in
p.000204: writing of the name and ad- dress of the facility at which the re- serve samples will be stored.
p.000204: (i) If a contract research organization conducting a bioavailability or bio- equivalence study that requires
p.000204: reserve sample retention under this section or
p.000204: § 320.63 goes out of business, it shall transfer its reserve samples to an ap- propriate, independent
p.000204: third party, and shall notify in writing the sponsor of the study of the transfer and provide the study
p.000204: sponsor with the name and address of the facility to which the re- serve samples have been transferred.
p.000204: [58 FR 25927, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000204:
p.000204: § 320.63 Retention of bioequivalence samples.
p.000204: The applicant of an abbreviated ap- plication or a supplemental application submitted under section 505 of the
p.000204: Fed- eral Food, Drug, and Cosmetic Act, or, if bioequivalence testing was per- formed under contract,
p.000204: the contract re- search organization shall retain re- serve samples of any test article and reference
p.000204: standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the ab-
p.000204: breviated application or supplemental application. The applicant or contract research organization shall
p.000204: retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall
p.000204: release the reserve samples to FDA upon request in accordance with
p.000204: § 320.38.
p.000204: [58 FR 25928, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000205: 205
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205: Pt. 328
p.000205: PART 328—OVER-THE-COUNTER DRUG PRODUCTS INTENDED FOR ORAL INGESTION THAT CONTAIN ALCOHOL
p.000205: Subpart A—General Provisions
p.000205: Sec.
p.000205: 328.1 Scope.
p.000205: 328.3 Definitions.
p.000205: Subpart B—Ingredients
p.000205: 328.10 Alcohol.
p.000205: Subpart C—Labeling
p.000205: 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain alcohol.
p.000205: AUTHORITY: Secs. 201, 301, 501, 502, 503, 505,
p.000205: 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
p.000205: SOURCE: 60 FR 13595, Mar. 13, 1995, unless
p.000205: otherwise noted.
p.000205: EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004.
p.000205:
p.000205: Subpart A—General Provisions
p.000205: § 328.1 Scope.
p.000205: Reference in this part to regulatory sections of the Code of Federal Regula- tions are to chapter I of title
p.000205: 21 unless otherwise noted.
p.000205: § 328.3 Definitions.
p.000205: As used in this part:
p.000205: (a) Alcohol means the substance known as ethanol, ethyl alcohol, or Al- cohol, USP.
p.000205: (b) Inactive ingredient means any com- ponent of a product other than an ac- tive ingredient as defined in §
p.000205: 210.3(b)(7) of this chapter.
p.000205: Subpart B—Ingredients
p.000205: § 328.10 Alcohol.
p.000205: (a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an
p.000205: inactive ingredient in concentrations that ex- ceed those established in this part, un- less a specific
p.000205: exemption, as provided in paragraph (e) or (f) of this section, has been approved.
p.000205: (b) For any OTC drug product in-
p.000205: tended for oral ingestion and labeled for use by adults and children 12 years
p.000205: 21 CFR Ch. I (4–1–12 Edition)
p.000205: of age and over, the amount of alcohol in the product shall not exceed 10 per- cent.
p.000205: (c) For any OTC drug product in- tended for oral ingestion and labeled for use by children 6 to
...
...
Searching for indicator substance:
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p.000204: § 320.38.
p.000204: [58 FR 25928, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000205: 205
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205: Pt. 328
p.000205: PART 328—OVER-THE-COUNTER DRUG PRODUCTS INTENDED FOR ORAL INGESTION THAT CONTAIN ALCOHOL
p.000205: Subpart A—General Provisions
p.000205: Sec.
p.000205: 328.1 Scope.
p.000205: 328.3 Definitions.
p.000205: Subpart B—Ingredients
p.000205: 328.10 Alcohol.
p.000205: Subpart C—Labeling
p.000205: 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain alcohol.
p.000205: AUTHORITY: Secs. 201, 301, 501, 502, 503, 505,
p.000205: 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
p.000205: SOURCE: 60 FR 13595, Mar. 13, 1995, unless
p.000205: otherwise noted.
p.000205: EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004.
p.000205:
p.000205: Subpart A—General Provisions
p.000205: § 328.1 Scope.
p.000205: Reference in this part to regulatory sections of the Code of Federal Regula- tions are to chapter I of title
p.000205: 21 unless otherwise noted.
p.000205: § 328.3 Definitions.
p.000205: As used in this part:
p.000205: (a) Alcohol means the substance known as ethanol, ethyl alcohol, or Al- cohol, USP.
p.000205: (b) Inactive ingredient means any com- ponent of a product other than an ac- tive ingredient as defined in §
p.000205: 210.3(b)(7) of this chapter.
p.000205: Subpart B—Ingredients
p.000205: § 328.10 Alcohol.
p.000205: (a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an
p.000205: inactive ingredient in concentrations that ex- ceed those established in this part, un- less a specific
p.000205: exemption, as provided in paragraph (e) or (f) of this section, has been approved.
p.000205: (b) For any OTC drug product in-
p.000205: tended for oral ingestion and labeled for use by adults and children 12 years
p.000205: 21 CFR Ch. I (4–1–12 Edition)
p.000205: of age and over, the amount of alcohol in the product shall not exceed 10 per- cent.
p.000205: (c) For any OTC drug product in- tended for oral ingestion and labeled for use by children 6 to
p.000205: under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent.
...
Health / ill
Searching for indicator ill:
(return to top)
p.000195: acceptable to FDA (usually a dissolu- tion rate test) that ensures human in vivo bioavailability.
p.000195: (6) Any other approach deemed ade- quate by FDA to measure bio- availability or
p.000195: establish bioequiva- lence.
p.000195: (c) FDA may, notwithstanding prior requirements for measuring bio- availability or establishing
p.000195: bioequiva- lence, require in vivo testing in hu- mans of a product at any time if the agency has
p.000195: evidence that the product:
p.000195: (1) May not produce therapeutic ef- fects comparable to a pharmaceutical equivalent or alternative with which
p.000195: it is intended to be used interchangeably;
p.000195: (2) May not be bioequivalent to a pharmaceutical equivalent or alter- native with which it is
p.000195: intended to be used interchangeably; or
p.000195: (3) Has greater than anticipated po- tential toxicity related to pharmaco- kinetic or other characteristics.
p.000195: [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July
p.000195: 1, 1992, as amended at 67 FR 77673, Dec. 19,
p.000195: 2002]
p.000195:
p.000195: § 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000195: (a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no
p.000195: unnecessary human re- search should be done.
p.000195: (2) An in vivo bioavailability study is generally done in a normal adult popu- lation under standardized
p.000195: conditions. In some situations, an in vivo bio- availability study in humans may pref- erably and more
p.000195: properly be done in suitable patients. Critically ill patients
p.000195: 21 CFR Ch. I (4–1–12 Edition)
p.000195: shall not be included in an in vivo bio- availability study unless the attending physician determines that there
p.000195: is a potential benefit to the patient.
p.000195: (b) Basic design. The basic design of an in vivo bioavailability study is de- termined by the following:
p.000195: (1) The scientific questions to be an- swered.
p.000195: (2) The nature of the reference mate- rial and the dosage form to be tested.
p.000195: (3) The availability of analytical methods.
p.000195: (4) Benefit-risk considerations in re- gard to testing in humans.
p.000195: (c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in
p.000195: comparison to an appropriate reference material unless some other approach is more appro- priate for
p.000195: valid scientific reasons.
p.000195: (d) Previously unmarketed active drug ingredients or therapeutic moieties. (1) An in vivo bioavailability
p.000195: study involving a drug product containing an active drug ingredient or therapeutic moiety that has not
p.000195: been approved for mar- keting can be used to measure the fol- lowing pharmacokinetic data:
p.000195: (i) The bioavailability of the formu- lation proposed for marketing; and
p.000195: (ii) The essential pharmacokinetic characteristics of the active drug in- gredient or therapeutic moiety,
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000203: (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure
p.000203: that the product meets a bioequivalence re- quirement shall be maintained by the manufacturer for at
p.000203: least 2 years after the expiration date of the batch and submitted to the Food and Drug Ad- ministration
p.000203: on request.
p.000203: (b) Any person who contracts with another party to conduct a bioequiva- lence study from which the data are
p.000203: in- tended to be submitted to FDA as part of an application submitted under part
p.000203: 314 of this chapter shall obtain from the person conducting the study suffi- cient accurate financial
p.000203: information to allow the submission of complete and accurate financial certifications or dis- closure statements
p.000203: required under part
p.000203: 54 of this chapter and shall maintain that information and all records relat- ing to the compensation
p.000203: given for that study and all other financial interest information required under part 54 of this chapter
p.000203: for 2 years after the date of approval of the application. The per- son maintaining these records shall,
p.000203: upon request for any properly author- ized officer or employee of the Food and Drug Administration, at
p.000203: reason- able time, permit such officer or em-
p.000203: 21 CFR Ch. I (4–1–12 Edition)
p.000203: ployee to have access to and copy and verify these records.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992, as amended at 63 FR
p.000203: 5252, Feb. 2, 1998]
p.000203:
p.000203: § 320.38 Retention of bioavailability samples.
p.000203: (a) The applicant of an application or supplemental application submitted under section 505 of the Federal
p.000203: Food, Drug, and Cosmetic Act, or, if bio- availability testing was performed under contract,
p.000203: the contract research organization shall retain an appro- priately identified reserve sample of the
p.000203: drug product for which the appli- cant is seeking approval (test article) and of the reference standard
p.000203: used to perform an in vivo bioavailability study in accordance with and for the studies described
p.000203: in paragraph (b) of this section that is representative of each sample of the test article and ref- erence
p.000203: standard provided by the appli- cant for the testing.
p.000203: (b) Reserve samples shall be retained for the following test articles and ref- erence standards and for the
p.000203: studies de- scribed:
p.000203: (1) If the formulation of the test arti- cle is the same as the formulation(s) used in the clinical
p.000203: studies dem- onstrating substantial evidence of safe- ty and effectiveness for the test arti- cle’s claimed
p.000203: indications, a reserve sample of the test article used to con- duct an in vivo bioavailability study
p.000203: comparing the test article to a ref- erence oral solution, suspension, or in- jection.
p.000203: (2) If the formulation of the test arti-
...
p.000203: article and of the reference standard used to conduct an in vivo bioequivalence study comparing the
p.000203: test article to the formulation(s) (ref- erence standard) used in the clinical studies.
p.000203: (3) For a new formulation, new dos-
p.000203: age form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved
p.000203: for mar- keting, a reserve sample of the test ar- ticle and of the reference standard used
p.000204: 204
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204: Food and Drug Administration, HHS § 320.63
p.000204:
p.000204:
p.000204: to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference
p.000204: standard) that contains the same active drug in- gredient or therapeutic moiety.
p.000204: (c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of
p.000204: the release tests required in the application or supplemental application.
p.000204: (d) Each reserve sample shall be ade- quately identified so that the reserve sample can be positively
p.000204: identified as having come from the same sample as used in the specific bioavailability study.
p.000204: (e) Each reserve sample shall be stored under conditions consistent with product labeling and in
p.000204: an area segregated from the area where testing is conducted and with access limited to authorized personnel.
p.000204: Each reserve sample shall be retained for a period of at least 5 years following the date on which the
p.000204: application or supplemental application is approved, or, if such ap- plication or supplemental application
p.000204: is not approved, at least 5 years fol- lowing the date of completion of the bioavailability study in which
p.000204: the sam- ple from which the reserve sample was obtained was used.
p.000204: (f) Authorized FDA personnel will or- dinarily collect reserve samples di- rectly from the applicant or
p.000204: contract research organization at the storage site during a preapproval inspection. If authorized FDA
p.000204: personnel are unable to collect samples, FDA may require the applicant or contract research or- ganization
p.000204: to submit the reserve sam- ples to the place identified in the agen- cy’s request. If FDA has not collected
p.000204: or requested delivery of a reserve sam- ple, or if FDA has not collected or re- quested delivery of any
p.000204: portion of a re- serve sample, the applicant or contract research organization shall retain the sample or
p.000204: remaining sample for the 5- year period specified in paragraph (e) of this section.
p.000204: (g) Upon release of the reserve sam-
p.000204: ples to FDA, the applicant or contract research organization shall provide a written assurance that, to
p.000204: the best knowledge and belief of the individual executing the assurance, the reserve samples came
p.000204: from the same samples
p.000204:
p.000204: as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall
...
Social / Age
Searching for indicator age:
(return to top)
p.000190: 320.32 Procedures for establishing or amend- ing a bioequivalence requirement.
p.000190: 320.33 Criteria and evidence to assess actual or potential bioequivalence problems.
p.000190: 320.34 Requirements for batch testing and certification by the Food and Drug Ad- ministration.
p.000190: 320.35 Requirements for in vitro testing of each batch.
p.000190: 320.36 Requirements for maintenance of records of bioequivalence testing.
p.000190: 320.38 Retention of bioavailability samples.
p.000190: 320.63 Retention of bioequivalence samples. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371.
p.000190: Subpart A—General Provisions
p.000190: § 320.1 Definitions.
p.000190: (a) Bioavailability means the rate and extent to which the active ingredient or active moiety is
p.000190: absorbed from a drug product and becomes available at the site of action. For drug products that are
p.000190: not intended to be absorbed
p.000190: 190
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190: Food and Drug Administration, HHS § 320.21
p.000190:
p.000190:
p.000190: into the bloodstream, bioavailability may be assessed by measurements in- tended to reflect the rate and
p.000190: extent to which the active ingredient or active moiety becomes available at the site of action.
p.000190: (b) Drug product means a finished dos- age form, e.g., tablet, capsule, or solu- tion, that contains the
p.000190: active drug in- gredient, generally, but not nec- essarily, in association with inactive
p.000190: ingredients.
p.000190: (c) Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of
p.000190: the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic
p.000190: moiety, or, in the case of modified release dosage forms that re- quire a reservoir or overage or
p.000190: such forms as prefilled syringes where resid- ual volume may vary, that deliver identical amounts of the
p.000190: active drug ingredient over the identical dosing pe- riod; do not necessarily contain the same inactive
p.000190: ingredients; and meet the identical compendial or other ap- plicable standard of identity, strength,
p.000190: quality, and purity, including potency and, where applicable, content uni- formity, disintegration
p.000190: times, and/or dissolution rates.
p.000190: (d) Pharmaceutical alternatives means
p.000190: drug products that contain the iden- tical therapeutic moiety, or its pre- cursor, but not necessarily
p.000190: in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets
p.000190: either the identical or its own respective compendial or other applicable standard of identity,
...
p.000194: forms that are not intended to deliver the active moiety to the bloodstream for systemic dis-
p.000194: tribution.
p.000194: (4) Well-controlled clinical trials that
p.000194: establish the safety and effectiveness of the drug product, for purposes of measuring
p.000194: bioavailability, or appro- priately designed comparative clinical trials, for purposes of demonstrating
p.000194: bioequivalence. This approach is the least accurate, sensitive, and reproduc- ible of the general
p.000194: approaches for measuring bioavailability or dem- onstrating bioequivalence. For dosage forms
p.000194: intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be con-
p.000194: sidered acceptable only when analyt- ical methods cannot be developed to permit use of one of
p.000194: the approaches
p.000195: 195
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195:
p.000195: § 320.25
p.000195: outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the ap- proaches described
p.000195: in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of this section are not available. This ap-
p.000195: proach may also be considered suffi- ciently accurate for measuring bio- availability or
p.000195: demonstrating bio- equivalence of dosage forms intended to deliver the active moiety locally, e.g.,
p.000195: topical preparations for the skin, eye, and mucous membranes; oral dos- age forms not intended to be
p.000195: absorbed, e.g., an antacid or radiopaque medium; and bronchodilators administered by inhalation if the onset
p.000195: and duration of pharmacological activity are defined.
p.000195: (5) A currently available in vitro test
p.000195: acceptable to FDA (usually a dissolu- tion rate test) that ensures human in vivo bioavailability.
p.000195: (6) Any other approach deemed ade- quate by FDA to measure bio- availability or
p.000195: establish bioequiva- lence.
p.000195: (c) FDA may, notwithstanding prior requirements for measuring bio- availability or establishing
p.000195: bioequiva- lence, require in vivo testing in hu- mans of a product at any time if the agency has
p.000195: evidence that the product:
p.000195: (1) May not produce therapeutic ef- fects comparable to a pharmaceutical equivalent or alternative with which
p.000195: it is intended to be used interchangeably;
p.000195: (2) May not be bioequivalent to a pharmaceutical equivalent or alter- native with which it is
p.000195: intended to be used interchangeably; or
p.000195: (3) Has greater than anticipated po- tential toxicity related to pharmaco- kinetic or other characteristics.
p.000195: [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July
p.000195: 1, 1992, as amended at 67 FR 77673, Dec. 19,
p.000195: 2002]
p.000195:
p.000195: § 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000195: (a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no
p.000195: unnecessary human re- search should be done.
p.000195: (2) An in vivo bioavailability study is generally done in a normal adult popu- lation under standardized
...
p.000203: the contract research organization shall retain an appro- priately identified reserve sample of the
p.000203: drug product for which the appli- cant is seeking approval (test article) and of the reference standard
p.000203: used to perform an in vivo bioavailability study in accordance with and for the studies described
p.000203: in paragraph (b) of this section that is representative of each sample of the test article and ref- erence
p.000203: standard provided by the appli- cant for the testing.
p.000203: (b) Reserve samples shall be retained for the following test articles and ref- erence standards and for the
p.000203: studies de- scribed:
p.000203: (1) If the formulation of the test arti- cle is the same as the formulation(s) used in the clinical
p.000203: studies dem- onstrating substantial evidence of safe- ty and effectiveness for the test arti- cle’s claimed
p.000203: indications, a reserve sample of the test article used to con- duct an in vivo bioavailability study
p.000203: comparing the test article to a ref- erence oral solution, suspension, or in- jection.
p.000203: (2) If the formulation of the test arti-
p.000203: cle differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety
p.000203: and ef- fectiveness for the test article’s claimed indications, a reserve sample of the test
p.000203: article and of the reference standard used to conduct an in vivo bioequivalence study comparing the
p.000203: test article to the formulation(s) (ref- erence standard) used in the clinical studies.
p.000203: (3) For a new formulation, new dos-
p.000203: age form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved
p.000203: for mar- keting, a reserve sample of the test ar- ticle and of the reference standard used
p.000204: 204
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204:
p.000204: Food and Drug Administration, HHS § 320.63
p.000204:
p.000204:
p.000204: to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference
p.000204: standard) that contains the same active drug in- gredient or therapeutic moiety.
p.000204: (c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of
p.000204: the release tests required in the application or supplemental application.
p.000204: (d) Each reserve sample shall be ade- quately identified so that the reserve sample can be positively
p.000204: identified as having come from the same sample as used in the specific bioavailability study.
p.000204: (e) Each reserve sample shall be stored under conditions consistent with product labeling and in
p.000204: an area segregated from the area where testing is conducted and with access limited to authorized personnel.
p.000204: Each reserve sample shall be retained for a period of at least 5 years following the date on which the
p.000204: application or supplemental application is approved, or, if such ap- plication or supplemental application
...
p.000205: 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
p.000205: SOURCE: 60 FR 13595, Mar. 13, 1995, unless
p.000205: otherwise noted.
p.000205: EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004.
p.000205:
p.000205: Subpart A—General Provisions
p.000205: § 328.1 Scope.
p.000205: Reference in this part to regulatory sections of the Code of Federal Regula- tions are to chapter I of title
p.000205: 21 unless otherwise noted.
p.000205: § 328.3 Definitions.
p.000205: As used in this part:
p.000205: (a) Alcohol means the substance known as ethanol, ethyl alcohol, or Al- cohol, USP.
p.000205: (b) Inactive ingredient means any com- ponent of a product other than an ac- tive ingredient as defined in §
p.000205: 210.3(b)(7) of this chapter.
p.000205: Subpart B—Ingredients
p.000205: § 328.10 Alcohol.
p.000205: (a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an
p.000205: inactive ingredient in concentrations that ex- ceed those established in this part, un- less a specific
p.000205: exemption, as provided in paragraph (e) or (f) of this section, has been approved.
p.000205: (b) For any OTC drug product in-
p.000205: tended for oral ingestion and labeled for use by adults and children 12 years
p.000205: 21 CFR Ch. I (4–1–12 Edition)
p.000205: of age and over, the amount of alcohol in the product shall not exceed 10 per- cent.
p.000205: (c) For any OTC drug product in- tended for oral ingestion and labeled for use by children 6 to
p.000205: under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent.
p.000205: (d) For any OTC drug product in- tended for oral ingestion and labeled for use by children under
p.000205: 6 years of age, the amount of alcohol in the prod- uct shall not exceed 0.5 percent.
p.000205: (e) The Food and Drug Administra- tion will grant an exemption from paragraphs (b), (c), and (d) of
p.000205: this sec- tion where appropriate, upon petition under the provisions of § 10.30 of this chapter.
p.000205: Appropriate cause, such as a specific solubility or manufacturing problem, must be adequately docu-
p.000205: mented in the petition. Decisions with respect to requests for exemption shall be maintained in a permanent
p.000205: file for public review by the Division of Dock- ets Management (HFA–305), Food and Drug Administration,
p.000205: 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
p.000205: (f) Ipecac syrup is exempt from the provisions of paragraph (d) of this sec- tion.
p.000205: (g) The following drugs are tempo- rarily exempt from the provisions of paragraphs (b), (c), and (d) of
p.000205: this sec- tion:
p.000205: (1) Aromatic Cascara Fluidextract.
p.000205: (2) Cascara Sagrada Fluidextract.
p.000205: (3) Orally ingested homeopathic drug products.
p.000205: [60 FR 13595, Mar. 13, 1995, as amended at 61
p.000205: FR 58630, Nov. 18, 1996; 68 FR 24879, May 9,
p.000205: 2003]
p.000205:
p.000205: Subpart C—Labeling
p.000205: § 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain
p.000205: alcohol.
p.000205: (a) The amount (percentage) of alco- hol present in a product shall be stated in terms of percent volume of
...
Social / Child
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p.000201: drug prod- ucts.
p.000201: (c) Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than
p.000201: a 2-fold dif- ference in median lethal dose (LD50)
p.000202: 202
p.000202:
p.000202:
p.000202:
p.000202:
p.000202:
p.000202:
p.000202:
p.000202: Food and Drug Administration, HHS § 320.34
p.000202:
p.000202:
p.000202: and median effective dose (ED50) val- ues, or have less than a 2-fold dif- ference in the
p.000202: minimum toxic con- centrations and minimum effective concentrations in the blood, and safe and
p.000202: effective use of the drug products requires careful dosage titration and patient monitoring.
p.000202: (d) Competent medical determination that a lack of bioequivalence would have a serious adverse effect
p.000202: in the treatment or prevention of a serious disease or condition.
p.000202: (e) Physicochemical evidence that:
p.000202: (1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter,
p.000202: or, if dis- solution in the stomach is critical to absorption, the volume of gastric fluids required to
p.000202: dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100
p.000202: milliliters for adults and prorated for infants and children).
p.000202: (2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in
p.000202: 30 minutes when tested using either a general method specified in an official compendium or a paddle
p.000202: method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37 C, or
p.000202: differs sig- nificantly from that of an appropriate reference material such as an identical drug product that
p.000202: is the subject of an approved full new drug application.
p.000202: (3) The particle size and/or surface area of the active drug ingredient is critical in
p.000202: determining its bio- availability.
p.000202: (4) Certain physical structural char- acteristics of the active drug ingre- dient, e.g., polymorphic
p.000202: forms, con- forms, solvates, complexes, and crystal modifications, dissolve poorly and this poor dissolution may
p.000202: affect absorption.
p.000202: (5) Such drug products have a high ratio of excipients to active ingredi- ents, e.g., greater than 5 to
p.000202: 1.
p.000202: (6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic excipients and lubricants, either may be
p.000202: required for absorption of the active drug ingre- dient or therapeutic moiety or, alter- natively, if present,
p.000202: may interfere with such absorption.
p.000202: (f) Pharmacokinetic evidence that:
...
p.000205: AUTHORITY: Secs. 201, 301, 501, 502, 503, 505,
p.000205: 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
p.000205: SOURCE: 60 FR 13595, Mar. 13, 1995, unless
p.000205: otherwise noted.
p.000205: EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004.
p.000205:
p.000205: Subpart A—General Provisions
p.000205: § 328.1 Scope.
p.000205: Reference in this part to regulatory sections of the Code of Federal Regula- tions are to chapter I of title
p.000205: 21 unless otherwise noted.
p.000205: § 328.3 Definitions.
p.000205: As used in this part:
p.000205: (a) Alcohol means the substance known as ethanol, ethyl alcohol, or Al- cohol, USP.
p.000205: (b) Inactive ingredient means any com- ponent of a product other than an ac- tive ingredient as defined in §
p.000205: 210.3(b)(7) of this chapter.
p.000205: Subpart B—Ingredients
p.000205: § 328.10 Alcohol.
p.000205: (a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an
p.000205: inactive ingredient in concentrations that ex- ceed those established in this part, un- less a specific
p.000205: exemption, as provided in paragraph (e) or (f) of this section, has been approved.
p.000205: (b) For any OTC drug product in-
p.000205: tended for oral ingestion and labeled for use by adults and children 12 years
p.000205: 21 CFR Ch. I (4–1–12 Edition)
p.000205: of age and over, the amount of alcohol in the product shall not exceed 10 per- cent.
p.000205: (c) For any OTC drug product in- tended for oral ingestion and labeled for use by children 6 to
p.000205: under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent.
p.000205: (d) For any OTC drug product in- tended for oral ingestion and labeled for use by children under
p.000205: 6 years of age, the amount of alcohol in the prod- uct shall not exceed 0.5 percent.
p.000205: (e) The Food and Drug Administra- tion will grant an exemption from paragraphs (b), (c), and (d) of
p.000205: this sec- tion where appropriate, upon petition under the provisions of § 10.30 of this chapter.
p.000205: Appropriate cause, such as a specific solubility or manufacturing problem, must be adequately docu-
p.000205: mented in the petition. Decisions with respect to requests for exemption shall be maintained in a permanent
p.000205: file for public review by the Division of Dock- ets Management (HFA–305), Food and Drug Administration,
p.000205: 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
p.000205: (f) Ipecac syrup is exempt from the provisions of paragraph (d) of this sec- tion.
p.000205: (g) The following drugs are tempo- rarily exempt from the provisions of paragraphs (b), (c), and (d) of
p.000205: this sec- tion:
p.000205: (1) Aromatic Cascara Fluidextract.
p.000205: (2) Cascara Sagrada Fluidextract.
p.000205: (3) Orally ingested homeopathic drug products.
p.000205: [60 FR 13595, Mar. 13, 1995, as amended at 61
p.000205: FR 58630, Nov. 18, 1996; 68 FR 24879, May 9,
p.000205: 2003]
p.000205:
p.000205: Subpart C—Labeling
p.000205: § 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain
p.000205: alcohol.
...
Social / Marital Status
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p.000190: (e) FDA will not publicly disclose the existence of a pending marketing appli- cation for a designated orphan drug for
p.000190: the use for which the drug was des- ignated unless the existence of the ap- plication has been
p.000190: previously publicly disclosed or acknowledged.
p.000190: (f) FDA will determine the public availability of data and information contained in pending
p.000190: and approved marketing applications for a des- ignated orphan drug for the use for which
p.000190: the drug was designated in ac- cordance with part 20 and § 314.430 of this chapter and other applicable
p.000190: stat- utes and regulations.
p.000190: Sec.
p.000190: 320.1 Definitions.
p.000190: Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products
p.000190: 320.21 Requirements for submission of bio- availability and bioequivalence data.
p.000190: 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.
p.000190: 320.23 Basis for measuring in vivo bio- availability or demonstrating bioequiva- lence.
p.000190: 320.24 Types of evidence to measure bio- availability or establish bioequivalence.
p.000190: 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000190: 320.26 Guidelines on the design of a single- dose in vivo bioavailability or bioequiva- lence study.
p.000190: 320.27 Guidelines on the design of a mul- tiple-dose in vivo bioavailability study.
p.000190: 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical evidence.
p.000190: 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study.
p.000190: 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- view of protocols by
p.000190: the Food and Drug Administration.
p.000190: 320.31 Applicability of requirements regard- ing an ‘‘Investigational New Drug Appli- cation.’’
p.000190: 320.32 Procedures for establishing or amend- ing a bioequivalence requirement.
p.000190: 320.33 Criteria and evidence to assess actual or potential bioequivalence problems.
p.000190: 320.34 Requirements for batch testing and certification by the Food and Drug Ad- ministration.
p.000190: 320.35 Requirements for in vitro testing of each batch.
p.000190: 320.36 Requirements for maintenance of records of bioequivalence testing.
p.000190: 320.38 Retention of bioavailability samples.
p.000190: 320.63 Retention of bioequivalence samples. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371.
p.000190: Subpart A—General Provisions
p.000190: § 320.1 Definitions.
p.000190: (a) Bioavailability means the rate and extent to which the active ingredient or active moiety is
...
p.000193: are not in- tended to be absorbed into the blood- stream, bioavailability may be as- sessed by
p.000193: measurements intended to re- flect the rate and extent to which the active ingredient or active moiety be-
p.000193: comes available at the site of action.
p.000193: (2) Statistical techniques used shall be of sufficient sensitivity to detect differences in rate and
p.000193: extent of ab- sorption that are not attributable to subject variability.
p.000193: (3) A drug product that differs from the reference material in its rate of ab- sorption, but not in its
p.000193: extent of ab- sorption, may be considered to be bio- available if the difference in the rate of absorption
p.000193: is intentional, is appro- priately reflected in the labeling, is not essential to the attainment of effective
p.000193: body drug concentrations on chronic use, and is considered medically insig- nificant for the drug product.
p.000193: (b) Two drug products will be consid- ered bioequivalent drug products if they are pharmaceutical equivalents
p.000193: or pharmaceutical alternatives whose rate and extent of absorption do not show a significant
p.000193: difference when ad- ministered at the same molar dose of the active moiety under similar experi- mental
p.000193: conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alter-
p.000193: natives may be equivalent in the ex- tent of their absorption but not in their rate of absorption and
p.000193: yet may be considered bioequivalent because such differences in the rate of absorption are
p.000193:
p.000194: 194
p.000194:
p.000194:
p.000194:
p.000194:
p.000194:
p.000194:
p.000194:
p.000194: Food and Drug Administration, HHS § 320.24
p.000194:
p.000194:
p.000194: intentional and are reflected in the la- beling, are not essential to the attain- ment of effective body
p.000194: drug concentra- tions on chronic use, and are consid- ered medically insignificant for the particular
p.000194: drug product studied.
p.000194: [57 FR 17999, Apr. 28, 1992, as amended at 67
p.000194: FR 77673, Dec. 19, 2002]
p.000194:
p.000194: § 320.24 Types of evidence to measure bioavailability or establish bio- equivalence.
p.000194: (a) Bioavailability may be measured or bioequivalence may be dem- onstrated by several in
p.000194: vivo and in vitro methods. FDA may require in vivo or in vitro testing, or both, to measure
p.000194: the bioavailability of a drug product or establish the bioequivalence of specific drug products. Information
p.000194: on bioequivalence requirements for specific products is included in the cur- rent edition of FDA’s publication
...
p.000195: (1) The scientific questions to be an- swered.
p.000195: (2) The nature of the reference mate- rial and the dosage form to be tested.
p.000195: (3) The availability of analytical methods.
p.000195: (4) Benefit-risk considerations in re- gard to testing in humans.
p.000195: (c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in
p.000195: comparison to an appropriate reference material unless some other approach is more appro- priate for
p.000195: valid scientific reasons.
p.000195: (d) Previously unmarketed active drug ingredients or therapeutic moieties. (1) An in vivo bioavailability
p.000195: study involving a drug product containing an active drug ingredient or therapeutic moiety that has not
p.000195: been approved for mar- keting can be used to measure the fol- lowing pharmacokinetic data:
p.000195: (i) The bioavailability of the formu- lation proposed for marketing; and
p.000195: (ii) The essential pharmacokinetic characteristics of the active drug in- gredient or therapeutic moiety,
p.000195: such as the rate of absorption, the extent of ab- sorption, the half-life of the thera- peutic moiety in
p.000195: vivo, and the rate of excretion and/or metabolism. Dose pro- portionality of the active drug ingre- dient or
p.000195: the therapeutic moiety needs to be established after single-dose ad- ministration and in certain instances
p.000195: after multiple-dose administration. This characterization is a necessary part of the investigation of
p.000195: the drug to support drug labeling.
p.000195: (2) The reference material in such a bioavailability study should be a solu- tion or suspension containing
p.000195: the same quantity of the active drug ingredient or therapeutic moiety as the formula- tion proposed for
p.000195: marketing.
p.000195: (3) The reference material should be administered by the same route as the formulation proposed for
p.000195: marketing unless an alternative or additional
p.000196: 196
p.000196:
p.000196:
p.000196:
p.000196:
p.000196:
p.000196:
p.000196:
p.000196: Food and Drug Administration, HHS § 320.25
p.000196:
p.000196:
p.000196: route is necessary to answer the sci- entific question under study. For ex- ample, in the case of an active
p.000196: drug in- gredient or therapeutic moiety that is poorly absorbed after oral administra- tion, it may be
p.000196: necessary to compare the oral dosage form proposed for mar- keting with the active drug ingredient or
p.000196: therapeutic moiety administered in solution both orally and intravenously.
p.000196: (e) Ne formulations of active drug in- gredients or therapeutic moieties approved for marketing. (1) An
...
p.000196: ingredient or therapeutic moiety and administered according to the dosage recommenda- tions in the
p.000196: labeling of the noncon- trolled release drug product.
p.000196: (iii) A currently marketed extended release drug product subject to an ap- proved full new drug
p.000196: application con- taining the same active drug ingre- dient or therapeutic moiety and admin- istered
p.000196: according to the dosage rec- ommendations in the labeling proposed for the extended release drug product.
p.000196: (iv) A reference material other than one set forth in paragraph (f)(2) (i), (ii) or (iii) of this section
p.000196: that is appro- priate for valid scientific reasons.
p.000196: (g) Combination drug products. (1) Gen- erally, the purpose of an in vivo bio- availability study involving a
p.000196: combina- tion drug product is to determine if the rate and extent of absorption of each active drug ingredient
p.000196: or therapeutic moiety in the combination drug prod- uct is equivalent to the rate and extent of absorption of
p.000196: each active drug ingre- dient or therapeutic moiety adminis- tered concurrently in separate single- ingredient
p.000196: preparations.
p.000196: (2) The reference material in such a bioavailability study should be two or more currently marketed,
p.000196: single-ingre- dient drug products each of which con- tains one of the active drug ingredients
p.000197: 197
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197:
p.000197: § 320.26
p.000197: or therapeutic moieties in the com- bination drug product. The Food and Drug Administration may,
p.000197: for valid scientific reasons, specify that the ref- erence material shall be a combination drug product that
p.000197: is the subject of an approved new drug application.
p.000197: (3) The Food and Drug Administra- tion may permit a bioavailability study involving a
p.000197: combination drug product to determine the rate and ex- tent of absorption of selected, but not all,
p.000197: active drug ingredients or thera- peutic moieties in the combination drug product. The Food and Drug
p.000197: Ad- ministration may permit this deter- mination if the pharmacokinetics and the interactions of the
p.000197: active drug in- gredients or therapeutic moieties in the combination drug product are well known and
...
p.000197: (h) Use of a placebo as the reference material. Where appropriate or where necessary to
p.000197: demonstrate the sensi- tivity of the test, the reference mate- rial in a bioavailability study may be a
p.000197: placebo if:
p.000197: (1) The study measures the thera- peutic or acute pharmacological effect of the active drug
p.000197: ingredient or thera- peutic moiety; or
p.000197: (2) The study is a clinical trial to es- tablish the safety and effectiveness of the drug product.
p.000197: (i) Standards for test drug product and reference material. (1) Both the drug product to be tested
p.000197: and the reference material, if it is another drug product, shall be shown to meet all compendial or
p.000197: other applicable standards of iden- tity, strength, quality, and purity, in- cluding potency and, where
p.000197: applicable, content uniformity, disintegration times, and dissolution rates.
p.000197: (2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same
p.000197: conditions as those used for full-scale production.
p.000197: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000197: 77674, Dec. 19, 2002]
p.000197: 21 CFR Ch. I (4–1–12 Edition)
p.000197:
p.000197: § 320.26 Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.
p.000197: (a) Basic principles. (1) An in vivo bio- availability or bioequivalence study should be a single-dose
p.000197: comparison of the drug product to be tested and the appropriate reference material con- ducted in
p.000197: normal adults.
p.000197: (2) The test product and the reference material should be administered to subjects in the fasting
p.000197: state, unless some other approach is more appro- priate for valid scientific reasons.
p.000197: (b) Study design. (1) A single-dose study should be crossover in design, unless a parallel design
p.000197: or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination
p.000197: period.
p.000197: (2) Unless some other approach is ap- propriate for valid scientific reasons, the drug elimination period
p.000197: should be either:
p.000197: (i) At least three times the half-life of the active drug ingredient or thera- peutic moiety, or its
p.000197: metabolite(s), measured in the blood or urine; or
p.000197: (ii) At least three times the half-life of decay of the acute pharmacological effect.
p.000197: (c) Collection of blood samples. (1) When comparison of the test product and the reference
p.000197: material is to be based on blood concentration time curves, unless some other approach is more
p.000197: appropriate for valid scientific reasons, blood samples should be taken with sufficient frequency to permit
p.000197: an estimate of both:
p.000197: (i) The peak concentration in the
p.000197: blood of the active drug ingredient or therapeutic moiety, or its metabo- lite(s), measured; and
p.000197: (ii) The total area under the curve for a time period at least three times the half-life of the active drug
p.000197: ingredient or therapeutic moiety, or its metabo- lite(s), measured.
p.000197: (2) In a study comparing oral dosage forms, the sampling times should be identical.
...
p.000198: cological effect to determine bio- availability may further require dem- onstration of dose-related
p.000198: response. In such a case, bioavailability may be de- termined by comparison of the dose-re- sponse curves as
p.000198: well as the total area under the acute pharmacological ef- fect-time curves for any given dose.
p.000198: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000198: 77674, Dec. 19, 2002]
p.000198:
p.000198: § 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study.
p.000198: (a) Basic principles. (1) In selected cir- cumstances it may be necessary for the test product and the reference
p.000198: material to be compared after repeated adminis- tration to determine steady-state lev- els of the active
p.000198: drug ingredient or therapeutic moiety in the body.
p.000198: (2) The test product and the reference
p.000198: material should be administered to subjects in the fasting or nonfasting state, depending upon the
p.000198: conditions
p.000198:
p.000198: reflected in the proposed labeling of the test product.
p.000198: (3) A multiple-dose study may be re- quired to determine the bioavailability of a drug product in the
p.000198: following cir- cumstances:
p.000198: (i) There is a difference in the rate of absorption but not in the extent of ab- sorption.
p.000198: (ii) There is excessive variability in bioavailability from subject to subject.
p.000198: (iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the
p.000198: blood re- sulting from a single dose is too low for accurate determination by the analyt- ical method.
p.000198: (iv) The drug product is an extended release dosage form.
p.000198: (b) Study design. (1) A multiple-dose study should be crossover in design, unless a parallel design or
p.000198: other design is more appropriate for valid scientific reasons, and should provide for a drug elimination
p.000198: period if steady-state con- ditions are not achieved.
p.000198: (2) A multiple-dose study is not re- quired to be of crossover design if the study is to establish
p.000198: dose proportion- ality under a multiple-dose regimen or to establish the pharmacokinetic pro- file of a
p.000198: new drug product, a new drug delivery system, or an extended release dosage form.
p.000198: (3) If a drug elimination period is re- quired, unless some other approach is more appropriate for
p.000198: valid scientific reasons, the drug elimination period should be either:
p.000198: (i) At least five times the half-life of the active drug ingredient or thera- peutic moiety, or
p.000198: its active metabo- lite(s), measured in the blood or urine; or
p.000198: (ii) At least five times the half-life of decay of the acute pharmacological ef- fect.
p.000198: (c) Achievement of steady-state condi- tions. Whenever a multiple-dose study is conducted, unless some
p.000198: other ap- proach is more appropriate for valid scientific reasons, sufficient doses of the test
p.000198: product and reference material should be administered in accordance with the labeling to achieve steady-
p.000198: state conditions.
p.000198: (d) Collection of blood or urine samples.
p.000198: (1) Whenever comparison of the test product and the reference material is
p.000199: 199
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199:
p.000199: § 320.28
p.000199: to be based on blood concentration- time curves at steady state, appro- priate dosage
p.000199: administration and sam- pling should be carried out to docu- ment attainment of steady state.
p.000199: (2) Whenever comparison of the test product and the reference material is to be based on cumulative
p.000199: urinary ex- cretion-time curves at steady state, ap- propriate dosage administration and sampling should be
p.000199: carried out to docu- ment attainment of steady state.
p.000199: (3) A more complete characterization of the blood concentration or urinary excretion rate during the
p.000199: absorption and elimination phases of a single dose administered at steady-state is encour- aged to permit estimation
p.000199: of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain
p.000199: pharmacokinetic information, e.g., half-life or blood clearance, that is essential in pre-
p.000199: paring adequate labeling for the drug product.
p.000199: (e) Steady-state parameters. (1) In cer- tain instances, e.g., in a study involv- ing a new drug entity,
p.000199: blood clearances at steady-state obtained in a multiple-
p.000199: dose study should be compared to blood clearances obtained in a single-dose study to support adequate
p.000199: dosage rec- ommendations.
p.000199: (2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a
p.000199: multiple- dose steady-state study is directly pro- portional to the fraction of the dose ab- sorbed and is
p.000199: equal to the cor- responding ‘‘zero to infinity’’ area under the curve for a single-dose study.
p.000199: Therefore, when steady-state condi- tions are achieved, a comparison of blood concentrations
p.000199: during a dosing interval may be used to define the frac- tion of the active drug ingredient or therapeutic
p.000199: moiety absorbed.
p.000199: (3) Other methods based on valid sci-
p.000199: entific reasons should be used to deter- mine the bioavailability of a drug prod- uct having dose-dependent
p.000199: kinetics (non-linear system).
p.000199: (f) Measurement of an acute pharma- cological effect. When comparison of the test product and the reference
p.000199: material is to be based on acute pharma- cological effect-time curves, measure- ments of this
p.000199: effect should be made with sufficient frequency to dem-
p.000199: 21 CFR Ch. I (4–1–12 Edition)
p.000199: onstrate a maximum effect and a lack of significant difference between the test product and the
p.000199: reference mate- rial.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.28 Correlation of bioavailability with an acute pharmacological ef- fect or clinical evidence.
p.000199: Correlation of in vivo bioavailability data with an acute pharmacological ef- fect or clinical evidence of
p.000199: safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g.,
p.000199: in the case of an extended release preparation.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.29 Analytical methods for an in vivo bioavailability or bioequiva- lence study.
p.000199: (a) The analytical method used in an in vivo bioavailability or bioequiva- lence study to measure the
p.000199: concentra- tion of the active drug ingredient or therapeutic moiety, or its active me- tabolite(s), in
p.000199: body fluids or excretory products, or the method used to meas- ure an acute pharmacological effect
p.000199: shall be demonstrated to be accurate and of sufficient sensitivity to meas- ure, with appropriate precision,
p.000199: the ac- tual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s),
p.000199: achieved in the body.
p.000199: (b) When the analytical method is not sensitive enough to measure accu- rately the concentration of
p.000199: the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or
p.000199: excretory products produced by a single dose of the test product, two or more single doses may be given
p.000199: together to produce higher concentra- tion if the requirements of § 320.31 are met.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.30 Inquiries regarding bio- availability and bioequivalence re- quirements and review of
p.000199: protocols by the Food and Drug Administra- tion.
p.000199: (a) The Commissioner of Food and Drugs strongly recommends that, to
p.000200: 200
p.000200:
p.000200:
p.000200:
p.000200:
p.000200:
p.000200:
p.000200:
p.000200: Food and Drug Administration, HHS § 320.31
p.000200:
p.000200:
p.000200: avoid the conduct of an improper study and unnecessary human research, any person planning to conduct a
p.000200: bio- availability or bioequivalence study submit the proposed protocol for the study to FDA for
p.000200: review prior to the initiation of the study.
p.000200: (b) FDA may review a proposed pro- tocol for a bioavailability or bioequiva- lence study and will offer
p.000200: advice with respect to whether the following condi- tions are met:
p.000200: (1) The design of the proposed bio- availability or bioequivalence study is appropriate.
p.000200: (2) The reference material to be used in the bioavailability or bioequivalence study is appropriate.
p.000200: (3) The proposed chemical and statis- tical analytical methods are adequate. (c)(1) General inquiries relating
p.000200: to in vivo bioavailability requirements and methodology shall be submitted to the Food and Drug
...
p.000200: Hampshire Ave., Silver Spring,
p.000200: MD 20993–0002.
p.000200: (2) General inquiries relating to bio- equivalence requirements and method- ology shall be submitted to
p.000200: the Food and Drug Administration, Center for Drug Evaluation and Research, Divi- sion of
p.000200: Bioequivalence (HFD–650), 7500 Standish Pl., Rockville, MD 20855–2773.
p.000200: [57 FR 18000, Apr. 28, 1992, as amended at 67
p.000200: FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26,
p.000200: 2009]
p.000200:
p.000200: § 320.31 Applicability of requirements regarding an ‘‘Investigational New Drug Application.’’
p.000200: (a) Any person planning to conduct an in vivo bioavailability or bioequiva- lence study in humans shall
p.000200: submit an ‘‘Investigational New Drug Applica- tion’’ (IND) if:
p.000200: (1) The test product contains a new chemical entity as defined in
p.000200: § 314.108(a) of this chapter; or
p.000200: (2) The study involves a radioactively labeled drug product; or
p.000200: (3) The study involves a cytotoxic drug product.
p.000200: (b) Any person planning to conduct a bioavailability or bioequivalence study in humans using a drug product that
p.000200: contains an already approved, non-new
p.000200:
p.000200: chemical entity shall submit an IND if the study is one of the following:
p.000200: (1) A single-dose study in normal sub- jects or patients where either the max- imum single or total daily dose exceeds
p.000200: that specified in the labeling of the drug product that is the subject of an approved new drug
p.000200: application or ab- breviated new drug application.
p.000200: (2) A multiple-dose study in normal subjects or patients where either the single or total daily dose
p.000200: exceeds that specified in the labeling of the drug product that is the subject of an ap- proved
p.000200: new drug application or abbre- viated new drug application.
p.000200: (3) A multiple-dose study on an ex- tended release product on which no sin- gle-dose study has been completed.
p.000200: (c) The provisions of parts 50, 56, and
p.000200: 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans
p.000200: conducted under an IND.
p.000200: (d) A bioavailability or bioequiva- lence study in humans other than one described in paragraphs (a)
p.000200: through (c) of this section is exempt from the re- quirements of part 312 of this chapter if the following
p.000200: conditions are satisfied:
p.000200: (1) If the study is one described under
p.000200: § 320.38(b) or § 320.63, the person con- ducting the study, including any con- tract research
p.000200: organization, must re- tain reserve samples of any test article and reference standard used in the study
p.000200: and release the reserve samples to FDA upon request, in accordance with, and for the period
p.000200: specified in,
p.000200: § 320.38;
p.000200: (2) An in vivo bioavailability or bio- equivalence study in humans must be conducted in compliance with
p.000200: the re- quirements for institutional review set forth in part 56 of this chapter, and in- formed consent set forth
p.000200: in part 50 of this chapter; and
...
Social / Police Officer
Searching for indicator officer:
(return to top)
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992]
p.000203:
p.000203: § 320.36 Requirements for mainte- nance of records of bioequivalence testing.
p.000203: (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure
p.000203: that the product meets a bioequivalence re- quirement shall be maintained by the manufacturer for at
p.000203: least 2 years after the expiration date of the batch and submitted to the Food and Drug Ad- ministration
p.000203: on request.
p.000203: (b) Any person who contracts with another party to conduct a bioequiva- lence study from which the data are
p.000203: in- tended to be submitted to FDA as part of an application submitted under part
p.000203: 314 of this chapter shall obtain from the person conducting the study suffi- cient accurate financial
p.000203: information to allow the submission of complete and accurate financial certifications or dis- closure statements
p.000203: required under part
p.000203: 54 of this chapter and shall maintain that information and all records relat- ing to the compensation
p.000203: given for that study and all other financial interest information required under part 54 of this chapter
p.000203: for 2 years after the date of approval of the application. The per- son maintaining these records shall,
p.000203: upon request for any properly author- ized officer or employee of the Food and Drug Administration, at
p.000203: reason- able time, permit such officer or em-
p.000203: 21 CFR Ch. I (4–1–12 Edition)
p.000203: ployee to have access to and copy and verify these records.
p.000203: [42 FR 1635, Jan. 7, 1977. Redesignated at 57
p.000203: FR 18001, Apr. 28, 1992, as amended at 63 FR
p.000203: 5252, Feb. 2, 1998]
p.000203:
p.000203: § 320.38 Retention of bioavailability samples.
p.000203: (a) The applicant of an application or supplemental application submitted under section 505 of the Federal
p.000203: Food, Drug, and Cosmetic Act, or, if bio- availability testing was performed under contract,
p.000203: the contract research organization shall retain an appro- priately identified reserve sample of the
p.000203: drug product for which the appli- cant is seeking approval (test article) and of the reference standard
p.000203: used to perform an in vivo bioavailability study in accordance with and for the studies described
p.000203: in paragraph (b) of this section that is representative of each sample of the test article and ref- erence
p.000203: standard provided by the appli- cant for the testing.
p.000203: (b) Reserve samples shall be retained for the following test articles and ref- erence standards and for the
p.000203: studies de- scribed:
p.000203: (1) If the formulation of the test arti- cle is the same as the formulation(s) used in the clinical
p.000203: studies dem- onstrating substantial evidence of safe- ty and effectiveness for the test arti- cle’s claimed
p.000203: indications, a reserve sample of the test article used to con- duct an in vivo bioavailability study
...
Social / Religion
Searching for indicator belief:
(return to top)
p.000204: (e) Each reserve sample shall be stored under conditions consistent with product labeling and in
p.000204: an area segregated from the area where testing is conducted and with access limited to authorized personnel.
p.000204: Each reserve sample shall be retained for a period of at least 5 years following the date on which the
p.000204: application or supplemental application is approved, or, if such ap- plication or supplemental application
p.000204: is not approved, at least 5 years fol- lowing the date of completion of the bioavailability study in which
p.000204: the sam- ple from which the reserve sample was obtained was used.
p.000204: (f) Authorized FDA personnel will or- dinarily collect reserve samples di- rectly from the applicant or
p.000204: contract research organization at the storage site during a preapproval inspection. If authorized FDA
p.000204: personnel are unable to collect samples, FDA may require the applicant or contract research or- ganization
p.000204: to submit the reserve sam- ples to the place identified in the agen- cy’s request. If FDA has not collected
p.000204: or requested delivery of a reserve sam- ple, or if FDA has not collected or re- quested delivery of any
p.000204: portion of a re- serve sample, the applicant or contract research organization shall retain the sample or
p.000204: remaining sample for the 5- year period specified in paragraph (e) of this section.
p.000204: (g) Upon release of the reserve sam-
p.000204: ples to FDA, the applicant or contract research organization shall provide a written assurance that, to
p.000204: the best knowledge and belief of the individual executing the assurance, the reserve samples came
p.000204: from the same samples
p.000204:
p.000204: as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall
p.000204: be exe- cuted by an individual authorized to act for the applicant or contract re- search organization in
p.000204: releasing the re- serve samples to FDA.
p.000204: (h) A contract research organization may contract with an appropriate, independent third party
p.000204: to provide storage of reserve samples provided that the sponsor of the study has been notified in
p.000204: writing of the name and ad- dress of the facility at which the re- serve samples will be stored.
p.000204: (i) If a contract research organization conducting a bioavailability or bio- equivalence study that requires
p.000204: reserve sample retention under this section or
p.000204: § 320.63 goes out of business, it shall transfer its reserve samples to an ap- propriate, independent
p.000204: third party, and shall notify in writing the sponsor of the study of the transfer and provide the study
p.000204: sponsor with the name and address of the facility to which the re- serve samples have been transferred.
p.000204: [58 FR 25927, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000204:
p.000204: § 320.63 Retention of bioequivalence samples.
p.000204: The applicant of an abbreviated ap- plication or a supplemental application submitted under section 505 of the
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.000190: an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain ex-
p.000190: tended release dosage forms), certain pharmaceutical equivalents or alter- natives may be considered
p.000190: bioequiva-
p.000190:
p.000190: lent if there is no significant difference in the extent to which the active ingre- dient or moiety from each
p.000190: product be- comes available at the site of drug ac- tion. This applies only if the difference in the rate at
p.000190: which the active ingre- dient or moiety becomes available at the site of drug action is intentional and
p.000190: is reflected in the proposed label- ing, is not essential to the attainment of effective body drug
p.000190: concentrations on chronic use, and is considered medi- cally insignificant for the drug.
p.000190: (f) Bioequivalence requirement means a
p.000190: requirement imposed by the Food and Drug Administration for in vitro and/or in vivo testing of specified drug
p.000190: prod- ucts which must be satisfied as a condi- tion of marketing.
p.000190: (g) Same drug product formulation means the formulation of the drug product submitted for
p.000190: approval and any formulations that have minor dif- ferences in composition or method of manufacture from
p.000190: the formulation sub- mitted for approval, but are similar enough to be relevant to the agency’s
p.000190: determination of bioequivalence.
p.000190: [42 FR 1634, Jan. 7, 1977, as amended at 42 FR
p.000190: 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67
p.000190: FR 77672, Dec. 19, 2002; 74 FR 2861, Jan. 16,
p.000190: 2009]
p.000190:
p.000190: Subpart B—Procedures for Deter- mining the Bioavailability or Bioequivalence of Drug Prod- ucts
p.000190: SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth-
p.000190: erwise noted.
p.000190:
p.000190: § 320.21 Requirements for submission of bioavailability and bioequiva- lence data.
p.000190: (a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall
p.000190: include in the application either:
p.000190: (1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application; or
p.000190: (2) Information to permit FDA to waive the submission of evidence meas- uring in vivo bioavailability.
p.000190: (b) Any person submitting an abbre- viated new drug application to FDA shall include in the
p.000190: application either:
p.000190: (1) Evidence demonstrating that the drug product that is the subject of the
p.000191: 191
p.000191:
p.000191:
p.000191:
p.000191:
p.000191:
p.000191:
p.000191:
p.000191:
p.000191: § 320.21
...
Social / orphan
Searching for indicator orphan:
(return to top)
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190: § 316.52
p.000190: Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
p.000190: [65 FR 56480, Sept. 19, 2000]
p.000190:
p.000190: 21 CFR Ch. I (4–1–12 Edition)
p.000190: PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
p.000190: Subpart A—General Provisions
p.000190:
p.000190: § 316.52 Availability for public disclo- sure of data and information in re- quests and applications.
p.000190: (a) FDA will not publicly disclose the existence of a request for orphan-drug designation under section 526 of the
p.000190: act prior to final FDA action on the re- quest unless the existence of the re- quest has been
p.000190: previously publicly dis- closed or acknowledged.
p.000190: (b) Whether or not the existence of a pending request for designation has been publicly disclosed
p.000190: or acknowl- edged, no data or information in the re- quest are available for public disclo- sure prior to
p.000190: final FDA action on the request.
p.000190: (c) Upon final FDA action on a re- quest for designation, FDA will deter- mine the public
p.000190: availability of data and information in the request in ac- cordance with part 20 and § 314.430 of this
p.000190: chapter and other applicable stat- utes and regulations.
p.000190: (d) In accordance with § 316.28, FDA will make a cumulative list of all or- phan drug designations
p.000190: available to the public and update such list monthly.
p.000190: (e) FDA will not publicly disclose the existence of a pending marketing appli- cation for a designated orphan drug for
p.000190: the use for which the drug was des- ignated unless the existence of the ap- plication has been
p.000190: previously publicly disclosed or acknowledged.
p.000190: (f) FDA will determine the public availability of data and information contained in pending
p.000190: and approved marketing applications for a des- ignated orphan drug for the use for which
p.000190: the drug was designated in ac- cordance with part 20 and § 314.430 of this chapter and other applicable
p.000190: stat- utes and regulations.
p.000190: Sec.
p.000190: 320.1 Definitions.
p.000190: Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products
p.000190: 320.21 Requirements for submission of bio- availability and bioequivalence data.
p.000190: 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.
p.000190: 320.23 Basis for measuring in vivo bio- availability or demonstrating bioequiva- lence.
p.000190: 320.24 Types of evidence to measure bio- availability or establish bioequivalence.
p.000190: 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000190: 320.26 Guidelines on the design of a single- dose in vivo bioavailability or bioequiva- lence study.
p.000190: 320.27 Guidelines on the design of a mul- tiple-dose in vivo bioavailability study.
p.000190: 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical evidence.
p.000190: 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study.
p.000190: 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- view of protocols by
p.000190: the Food and Drug Administration.
...
Economic / Economic/Poverty
Searching for indicator poor:
(return to top)
p.000202: (e) Physicochemical evidence that:
p.000202: (1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter,
p.000202: or, if dis- solution in the stomach is critical to absorption, the volume of gastric fluids required to
p.000202: dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100
p.000202: milliliters for adults and prorated for infants and children).
p.000202: (2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in
p.000202: 30 minutes when tested using either a general method specified in an official compendium or a paddle
p.000202: method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37 C, or
p.000202: differs sig- nificantly from that of an appropriate reference material such as an identical drug product that
p.000202: is the subject of an approved full new drug application.
p.000202: (3) The particle size and/or surface area of the active drug ingredient is critical in
p.000202: determining its bio- availability.
p.000202: (4) Certain physical structural char- acteristics of the active drug ingre- dient, e.g., polymorphic
p.000202: forms, con- forms, solvates, complexes, and crystal modifications, dissolve poorly and this poor dissolution may
p.000202: affect absorption.
p.000202: (5) Such drug products have a high ratio of excipients to active ingredi- ents, e.g., greater than 5 to
p.000202: 1.
p.000202: (6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic excipients and lubricants, either may be
p.000202: required for absorption of the active drug ingre- dient or therapeutic moiety or, alter- natively, if present,
p.000202: may interfere with such absorption.
p.000202: (f) Pharmacokinetic evidence that:
p.000202: (1) The active drug ingredient, thera- peutic moiety, or its precursor is ab-
p.000202:
p.000202: sorbed in large part in a particular seg- ment of the gastrointestinal tract or is absorbed from a localized site.
p.000202: (2) The degree of absorption of the ac- tive drug ingredient, therapeutic moi- ety, or its precursor is poor,
p.000202: e.g., less than 50 percent, ordinarily in compari- son to an intravenous dose, even when it is administered
p.000202: in pure form, e.g., in solution.
p.000202: (3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the
p.000202: process of ab- sorption (first-class metabolism) so the therapeutic effect and/or toxicity of such drug
p.000202: product is determined by the rate as well as the degree of absorp- tion.
p.000202: (4) The therapeutic moiety is rapidly
p.000202: metabolized or excreted so that rapid dissolution and absorption are required for effectiveness.
p.000202: (5) The active drug ingredient or therapeutic moiety is unstable in spe- cific portions of the
p.000202: gastrointestinal tract and requires special coatings or formulations, e.g., buffers, enteric coatings,
p.000202: and film coatings, to assure adequate absorption.
p.000202: (6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the
p.000202: rate and ex- tent of absorption are important to bioequivalence.
p.000202: [42 FR 1635, Jan. 7, 1977. Redesignated and
p.000202: amended at 57 FR 18001, Apr. 28, 1992]
p.000202:
p.000202: § 320.34 Requirements for batch test- ing and certification by the Food and Drug Administration.
p.000202: (a) If the Commissioner determines that individual batch testing by the Food and Drug Administration
...
General/Other / Dependent
Searching for indicator dependent:
(return to top)
p.000199: of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain
p.000199: pharmacokinetic information, e.g., half-life or blood clearance, that is essential in pre-
p.000199: paring adequate labeling for the drug product.
p.000199: (e) Steady-state parameters. (1) In cer- tain instances, e.g., in a study involv- ing a new drug entity,
p.000199: blood clearances at steady-state obtained in a multiple-
p.000199: dose study should be compared to blood clearances obtained in a single-dose study to support adequate
p.000199: dosage rec- ommendations.
p.000199: (2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a
p.000199: multiple- dose steady-state study is directly pro- portional to the fraction of the dose ab- sorbed and is
p.000199: equal to the cor- responding ‘‘zero to infinity’’ area under the curve for a single-dose study.
p.000199: Therefore, when steady-state condi- tions are achieved, a comparison of blood concentrations
p.000199: during a dosing interval may be used to define the frac- tion of the active drug ingredient or therapeutic
p.000199: moiety absorbed.
p.000199: (3) Other methods based on valid sci-
p.000199: entific reasons should be used to deter- mine the bioavailability of a drug prod- uct having dose-dependent
p.000199: kinetics (non-linear system).
p.000199: (f) Measurement of an acute pharma- cological effect. When comparison of the test product and the reference
p.000199: material is to be based on acute pharma- cological effect-time curves, measure- ments of this
p.000199: effect should be made with sufficient frequency to dem-
p.000199: 21 CFR Ch. I (4–1–12 Edition)
p.000199: onstrate a maximum effect and a lack of significant difference between the test product and the
p.000199: reference mate- rial.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.28 Correlation of bioavailability with an acute pharmacological ef- fect or clinical evidence.
p.000199: Correlation of in vivo bioavailability data with an acute pharmacological ef- fect or clinical evidence of
p.000199: safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g.,
p.000199: in the case of an extended release preparation.
p.000199: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000199: 77674, Dec. 19, 2002]
p.000199:
p.000199: § 320.29 Analytical methods for an in vivo bioavailability or bioequiva- lence study.
p.000199: (a) The analytical method used in an in vivo bioavailability or bioequiva- lence study to measure the
p.000199: concentra- tion of the active drug ingredient or therapeutic moiety, or its active me- tabolite(s), in
p.000199: body fluids or excretory products, or the method used to meas- ure an acute pharmacological effect
p.000199: shall be demonstrated to be accurate and of sufficient sensitivity to meas- ure, with appropriate precision,
...
p.000202: may interfere with such absorption.
p.000202: (f) Pharmacokinetic evidence that:
p.000202: (1) The active drug ingredient, thera- peutic moiety, or its precursor is ab-
p.000202:
p.000202: sorbed in large part in a particular seg- ment of the gastrointestinal tract or is absorbed from a localized site.
p.000202: (2) The degree of absorption of the ac- tive drug ingredient, therapeutic moi- ety, or its precursor is poor,
p.000202: e.g., less than 50 percent, ordinarily in compari- son to an intravenous dose, even when it is administered
p.000202: in pure form, e.g., in solution.
p.000202: (3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the
p.000202: process of ab- sorption (first-class metabolism) so the therapeutic effect and/or toxicity of such drug
p.000202: product is determined by the rate as well as the degree of absorp- tion.
p.000202: (4) The therapeutic moiety is rapidly
p.000202: metabolized or excreted so that rapid dissolution and absorption are required for effectiveness.
p.000202: (5) The active drug ingredient or therapeutic moiety is unstable in spe- cific portions of the
p.000202: gastrointestinal tract and requires special coatings or formulations, e.g., buffers, enteric coatings,
p.000202: and film coatings, to assure adequate absorption.
p.000202: (6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the
p.000202: rate and ex- tent of absorption are important to bioequivalence.
p.000202: [42 FR 1635, Jan. 7, 1977. Redesignated and
p.000202: amended at 57 FR 18001, Apr. 28, 1992]
p.000202:
p.000202: § 320.34 Requirements for batch test- ing and certification by the Food and Drug Administration.
p.000202: (a) If the Commissioner determines that individual batch testing by the Food and Drug Administration
p.000202: is nec- essary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall
p.000202: include in the bioequivalence requirement a require- ment for manufacturers to submit sam- ples of each
p.000202: batch to the Food and Drug Administration and to withhold distribution of the batch until notified by
p.000202: the Food and Drug Administration that the batch may be introduced into interstate commerce.
p.000202: (b) The Commissioner will ordinarily
p.000202: terminate a requirement for a manu- facturer to submit samples for batch testing on a finding that the
p.000202: manufac- turer has produced four consecutive
p.000203: 203
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203:
p.000203: § 320.35
p.000203: batches that were tested by the Food and Drug Administration and found to meet the bioequivalence
p.000203: requirement, unless the public health requires that batch testing be extended to additional batches.
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.000190: 320.23 Basis for measuring in vivo bio- availability or demonstrating bioequiva- lence.
p.000190: 320.24 Types of evidence to measure bio- availability or establish bioequivalence.
p.000190: 320.25 Guidelines for the conduct of an in vivo bioavailability study.
p.000190: 320.26 Guidelines on the design of a single- dose in vivo bioavailability or bioequiva- lence study.
p.000190: 320.27 Guidelines on the design of a mul- tiple-dose in vivo bioavailability study.
p.000190: 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical evidence.
p.000190: 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study.
p.000190: 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- view of protocols by
p.000190: the Food and Drug Administration.
p.000190: 320.31 Applicability of requirements regard- ing an ‘‘Investigational New Drug Appli- cation.’’
p.000190: 320.32 Procedures for establishing or amend- ing a bioequivalence requirement.
p.000190: 320.33 Criteria and evidence to assess actual or potential bioequivalence problems.
p.000190: 320.34 Requirements for batch testing and certification by the Food and Drug Ad- ministration.
p.000190: 320.35 Requirements for in vitro testing of each batch.
p.000190: 320.36 Requirements for maintenance of records of bioequivalence testing.
p.000190: 320.38 Retention of bioavailability samples.
p.000190: 320.63 Retention of bioequivalence samples. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371.
p.000190: Subpart A—General Provisions
p.000190: § 320.1 Definitions.
p.000190: (a) Bioavailability means the rate and extent to which the active ingredient or active moiety is
p.000190: absorbed from a drug product and becomes available at the site of action. For drug products that are
p.000190: not intended to be absorbed
p.000190: 190
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190:
p.000190: Food and Drug Administration, HHS § 320.21
p.000190:
p.000190:
p.000190: into the bloodstream, bioavailability may be assessed by measurements in- tended to reflect the rate and
p.000190: extent to which the active ingredient or active moiety becomes available at the site of action.
p.000190: (b) Drug product means a finished dos- age form, e.g., tablet, capsule, or solu- tion, that contains the
p.000190: active drug in- gredient, generally, but not nec- essarily, in association with inactive
p.000190: ingredients.
p.000190: (c) Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of
p.000190: the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic
...
p.000204: [58 FR 25927, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000204:
p.000204: § 320.63 Retention of bioequivalence samples.
p.000204: The applicant of an abbreviated ap- plication or a supplemental application submitted under section 505 of the
p.000204: Fed- eral Food, Drug, and Cosmetic Act, or, if bioequivalence testing was per- formed under contract,
p.000204: the contract re- search organization shall retain re- serve samples of any test article and reference
p.000204: standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the ab-
p.000204: breviated application or supplemental application. The applicant or contract research organization shall
p.000204: retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall
p.000204: release the reserve samples to FDA upon request in accordance with
p.000204: § 320.38.
p.000204: [58 FR 25928, Apr. 28, 1993, as amended at 64
p.000204: FR 402, Jan. 5, 1999]
p.000205: 205
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205:
p.000205: Pt. 328
p.000205: PART 328—OVER-THE-COUNTER DRUG PRODUCTS INTENDED FOR ORAL INGESTION THAT CONTAIN ALCOHOL
p.000205: Subpart A—General Provisions
p.000205: Sec.
p.000205: 328.1 Scope.
p.000205: 328.3 Definitions.
p.000205: Subpart B—Ingredients
p.000205: 328.10 Alcohol.
p.000205: Subpart C—Labeling
p.000205: 328.50 Principal display panel of all OTC drug products intended for oral ingestion that contain alcohol.
p.000205: AUTHORITY: Secs. 201, 301, 501, 502, 503, 505,
p.000205: 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
p.000205: SOURCE: 60 FR 13595, Mar. 13, 1995, unless
p.000205: otherwise noted.
p.000205: EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004.
p.000205:
p.000205: Subpart A—General Provisions
p.000205: § 328.1 Scope.
p.000205: Reference in this part to regulatory sections of the Code of Federal Regula- tions are to chapter I of title
p.000205: 21 unless otherwise noted.
p.000205: § 328.3 Definitions.
p.000205: As used in this part:
p.000205: (a) Alcohol means the substance known as ethanol, ethyl alcohol, or Al- cohol, USP.
p.000205: (b) Inactive ingredient means any com- ponent of a product other than an ac- tive ingredient as defined in §
p.000205: 210.3(b)(7) of this chapter.
p.000205: Subpart B—Ingredients
p.000205: § 328.10 Alcohol.
p.000205: (a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an
p.000205: inactive ingredient in concentrations that ex- ceed those established in this part, un- less a specific
p.000205: exemption, as provided in paragraph (e) or (f) of this section, has been approved.
p.000205: (b) For any OTC drug product in-
p.000205: tended for oral ingestion and labeled for use by adults and children 12 years
p.000205: 21 CFR Ch. I (4–1–12 Edition)
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000197: for valid scientific reasons, specify that the ref- erence material shall be a combination drug product that
p.000197: is the subject of an approved new drug application.
p.000197: (3) The Food and Drug Administra- tion may permit a bioavailability study involving a
p.000197: combination drug product to determine the rate and ex- tent of absorption of selected, but not all,
p.000197: active drug ingredients or thera- peutic moieties in the combination drug product. The Food and Drug
p.000197: Ad- ministration may permit this deter- mination if the pharmacokinetics and the interactions of the
p.000197: active drug in- gredients or therapeutic moieties in the combination drug product are well known and
p.000197: the therapeutic activity of the combination drug product is gen- erally recognized to reside in only one
p.000197: of the active drug ingredients or thera- peutic moieties, e.g., ampicillin in an ampicillin-probenecid
p.000197: combination drug product.
p.000197: (h) Use of a placebo as the reference material. Where appropriate or where necessary to
p.000197: demonstrate the sensi- tivity of the test, the reference mate- rial in a bioavailability study may be a
p.000197: placebo if:
p.000197: (1) The study measures the thera- peutic or acute pharmacological effect of the active drug
p.000197: ingredient or thera- peutic moiety; or
p.000197: (2) The study is a clinical trial to es- tablish the safety and effectiveness of the drug product.
p.000197: (i) Standards for test drug product and reference material. (1) Both the drug product to be tested
p.000197: and the reference material, if it is another drug product, shall be shown to meet all compendial or
p.000197: other applicable standards of iden- tity, strength, quality, and purity, in- cluding potency and, where
p.000197: applicable, content uniformity, disintegration times, and dissolution rates.
p.000197: (2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same
p.000197: conditions as those used for full-scale production.
p.000197: [42 FR 1648, Jan. 7, 1977, as amended at 67 FR
p.000197: 77674, Dec. 19, 2002]
p.000197: 21 CFR Ch. I (4–1–12 Edition)
p.000197:
p.000197: § 320.26 Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.
p.000197: (a) Basic principles. (1) An in vivo bio- availability or bioequivalence study should be a single-dose
...
Orphaned Trigger Words
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| belief | Religion |
| children | Child |
| dependent | Dependent |
| drug | Drug Usage |
| ill | ill |
| minor | Youth/Minors |
| nation | stateless persons |
| native | Indigenous |
| officer | Police Officer |
| orphan | orphan |
| party | political affiliation |
| placebo | participants in a control group |
| poor | Economic/Poverty |
| single | Marital Status |
| substance | Drug Usage |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| drug | ['substance'] |
| substance | ['drug'] |
Trigger Words
consent
protection
risk
sensitive
Applicable Type / Vulnerability / Indicator Overlay for this Input