cfr_sections
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19 rows where part_number = 320 and title_number = 21 sorted by section_id
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| section_id ▼ | title_number | title_name | chapter | subchapter | part_number | part_name | subpart | subpart_name | section_number | section_heading | agency | authority | source_citation | amendment_citations | full_text |
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| 21:21:5.0.1.1.8.1.1.1 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | A | Subpart A—General Provisions | § 320.1 Definitions. | FDA | [81 FR 69658, Oct. 6, 2016] | The definitions contained in § 314.3 of this chapter apply to those terms when used in this part. | |||
| 21:21:5.0.1.1.8.2.1.1 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.21 Requirements for submission of bioavailability and bioequivalence data. | FDA | [57 FR 17998, Apr. 28, 1992, as amended at 67 FR 77672, Dec. 19, 2002; 74 FR 2862, Jan. 16, 2009] | (a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall include in the application either: (1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application; or (2) Information to permit FDA to waive the submission of evidence measuring in vivo bioavailability. (b) Any person submitting an abbreviated new drug application to FDA shall include in the application either: (1) Evidence demonstrating that the drug product that is the subject of the abbreviated new drug application is bioequivalent to the reference listed drug (defined in § 314.3(b) of this chapter). A complete study report must be submitted for the bioequivalence study upon which the applicant relies for approval. For all other bioequivalence studies conducted on the same drug product formulation, the applicant must submit either a complete or summary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may require that the applicant submit a complete report of the bioequivalence study to FDA; or (2) Information to show that the drug product is bioequivalent to the reference listed drug which would permit FDA to waive the submission of evidence demonstrating in vivo bioequivalence as provided in paragraph (f) of this section. (c) Any person submitting a supplemental application to FDA shall include in the supplemental application the evidence or information set forth in paragraphs (a) and (b) of this section if the supplemental application proposes any of the following changes: (1) A change in the manufacturing site or a change in the manufacturing process, including a change in product formulation or dosage strength, beyond the variations provided for in the approved application. (2) A change in the labeling to provide for a new indication for use of the drug product, if clinical studies are required to support the new indication for use. (3) A cha… | |||
| 21:21:5.0.1.1.8.2.1.10 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.30 Inquiries regarding bioavailability and bioequivalence requirements and review of protocols by the Food and Drug Administration. | FDA | [57 FR 18000, Apr. 28, 1992, as amended at 67 FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26, 2009] | (a) The Commissioner of Food and Drugs strongly recommends that, to avoid the conduct of an improper study and unnecessary human research, any person planning to conduct a bioavailability or bioequivalence study submit the proposed protocol for the study to FDA for review prior to the initiation of the study. (b) FDA may review a proposed protocol for a bioavailability or bioequivalence study and will offer advice with respect to whether the following conditions are met: (1) The design of the proposed bioavailability or bioequivalence study is appropriate. (2) The reference material to be used in the bioavailability or bioequivalence study is appropriate. (3) The proposed chemical and statistical analytical methods are adequate. (c)(1) General inquiries relating to in vivo bioavailability requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002. (2) General inquiries relating to bioequivalence requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Bioequivalence (HFD-650), 7500 Standish Pl., Rockville, MD 20855-2773. | |||
| 21:21:5.0.1.1.8.2.1.11 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.31 Applicability of requirements regarding an “Investigational New Drug Application.” | FDA | [57 FR 18000, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, 2002; 75 FR 59963, Sept. 29, 2010] | (a) Any person planning to conduct an in vivo bioavailability or bioequivalence study in humans shall submit an “Investigational New Drug Application” (IND) if: (1) The test product contains a new chemical entity as defined in § 314.108(a) of this chapter; or (2) The study involves a radioactively labeled drug product; or (3) The study involves a cytotoxic drug product. (b) Any person planning to conduct a bioavailability or bioequivalence study in humans using a drug product that contains an already approved, non-new chemical entity shall submit an IND if the study is one of the following: (1) A single-dose study in normal subjects or patients where either the maximum single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or abbreviated new drug application. (2) A multiple-dose study in normal subjects or patients where either the single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or abbreviated new drug application. (3) A multiple-dose study on an extended release product on which no single-dose study has been completed. (c) The provisions of parts 50, 56, and 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans conducted under an IND. (d) A bioavailability or bioequivalence study in humans other than one described in paragraphs (a) through (c) of this section is exempt from the requirements of part 312 of this chapter if the following conditions are satisfied: (1) If the study is one described under § 320.38(b) or § 320.63, the person conducting the study, including any contract research organization, must retain reserve samples of any test article and reference standard used in the study and release the reserve samples to FDA upon request, in accordance with, and for the period specified in, § 320.38; (2) An in vivo bioavailability or bioequivalence study in humans must be conducted in… | |||
| 21:21:5.0.1.1.8.2.1.12 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.32 Procedures for establishing or amending a bioequivalence requirement. | FDA | [57 FR 18000, Apr. 28, 1992] | (a) The Food and Drug Administration, on its own initiative or in response to a petition by an interested person, may propose and promulgate a regulation to establish a bioequivalence requirement for a product not subject to section 505(j) of the act if it finds there is well-documented evidence that specific pharmaceutical equivalents or pharmaceutical alternatives intended to be used interchangeably for the same therapeutic effect: (1) Are not bioequivalent drug products; or (2) May not be bioequivalent drug products based on the criteria set forth in § 320.33; or (3) May not be bioequivalent drug products because they are members of a class of drug products that have close structural similarity and similar physicochemical or pharmacokinetic properties to other drug products in the same class that FDA finds are not bioequivalent drug products. (b) FDA shall include in a proposed rule to establish a bioequivalence requirement the evidence and criteria set forth in § 320.33 that are to be considered in determining whether to issue the proposal. If the rulemaking is proposed in response to a petition, FDA shall include in the proposal a summary and analysis of the relevant information that was submitted in the petition as well as other available information to support the establishment of a bioequivalence requirement. (c) FDA, on its own initiative or in response to a petition by an interested person, may propose and promulgate an amendment to a bioequivalence requirement established under this subpart. | |||
| 21:21:5.0.1.1.8.2.1.13 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.33 Criteria and evidence to assess actual or potential bioequivalence problems. | FDA | [42 FR 1635, Jan. 7, 1977. Redesignated and amended at 57 FR 18001, Apr. 28, 1992; 81 FR 17066, Mar. 28, 2016] | The Commissioner of Food and Drugs shall consider the following factors, when supported by well-documented evidence, to identify specific pharmaceutical equivalents and pharmaceutical alternatives that are not or may not be bioequivalent drug products. (a) Evidence from well-controlled clinical trials or controlled observations in patients that such drug products do not give comparable therapeutic effects. (b) Evidence from well-controlled bioequivalence studies that such products are not bioequivalent drug products. (c) Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2-fold difference in median lethal dose (LD 50 ) and median effective dose (ED 50 ) values, or have less than a 2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood, and safe and effective use of the drug products requires careful dosage titration and patient monitoring. (d) Competent medical determination that a lack of bioequivalence would have a serious adverse effect in the treatment or prevention of a serious disease or condition. (e) Physicochemical evidence that: (1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter, or, if dissolution in the stomach is critical to absorption, the volume of gastric fluids required to dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100 milliliters for adults and prorated for infants and children). (2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in 30 minutes when tested using either a general method specified in an official compendium or a paddle method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37 °C, or differs significantly from that of an appropriate reference material such as an identical drug product that is the subject of an approved full new drug application. (3) The particle size and/or surface area of the active … | |||
| 21:21:5.0.1.1.8.2.1.14 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.34 Requirements for batch testing and certification by the Food and Drug Administration. | FDA | [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992] | (a) If the Commissioner determines that individual batch testing by the Food and Drug Administration is necessary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall include in the bioequivalence requirement a requirement for manufacturers to submit samples of each batch to the Food and Drug Administration and to withhold distribution of the batch until notified by the Food and Drug Administration that the batch may be introduced into interstate commerce. (b) The Commissioner will ordinarily terminate a requirement for a manufacturer to submit samples for batch testing on a finding that the manufacturer has produced four consecutive batches that were tested by the Food and Drug Administration and found to meet the bioequivalence requirement, unless the public health requires that batch testing be extended to additional batches. | |||
| 21:21:5.0.1.1.8.2.1.15 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.35 Requirements for in vitro testing of each batch. | FDA | [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992] | If a bioequivalence requirement specifies a currently available in vitro test or an in vitro bioequivalence standard comparing the drug product to a reference standard, the manufacturer shall conduct the test on a sample of each batch of the drug product to assure batch-to-batch uniformity. | |||
| 21:21:5.0.1.1.8.2.1.16 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.36 Requirements for maintenance of records of bioequivalence testing. | FDA | [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992, as amended at 63 FR 5252, Feb. 2, 1998] | (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure that the product meets a bioequivalence requirement shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitted to the Food and Drug Administration on request. (b) Any person who contracts with another party to conduct a bioequivalence study from which the data are intended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study sufficient accurate financial information to allow the submission of complete and accurate financial certifications or disclosure statements required under part 54 of this chapter and shall maintain that information and all records relating to the compensation given for that study and all other financial interest information required under part 54 of this chapter for 2 years after the date of approval of the application. The person maintaining these records shall, upon request for any properly authorized officer or employee of the Food and Drug Administration, at reasonable time, permit such officer or employee to have access to and copy and verify these records. | |||
| 21:21:5.0.1.1.8.2.1.17 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.38 Retention of bioavailability samples. | FDA | [58 FR 25927, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999] | (a) The applicant of an application or supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drug product for which the applicant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and reference standard provided by the applicant for the testing. (b) Reserve samples shall be retained for the following test articles and reference standards and for the studies described: (1) If the formulation of the test article is the same as the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection. (2) If the formulation of the test article differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the clinical studies. (3) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety. (c) Each reserve sample shall consist of a suff… | |||
| 21:21:5.0.1.1.8.2.1.18 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.63 Retention of bioequivalence samples. | FDA | [58 FR 25928, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999] | The applicant of an abbreviated application or a supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall release the reserve samples to FDA upon request in accordance with § 320.38. | |||
| 21:21:5.0.1.1.8.2.1.2 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence. | FDA | [57 FR 17998, Apr. 28, 1992, as amended at 67 FR 77673, Dec. 19, 2002] | (a) Any person submitting a full or abbreviated new drug application, or a supplemental application proposing any of the changes set forth in § 320.21(c), may request FDA to waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of the drug product that is the subject of the application. An applicant shall submit a request for waiver with the application. Except as provided in paragraph (f) of this section, FDA shall waive the requirement for the submission of evidence of in vivo bioavailability or bioequivalence if the drug product meets any of the provisions of paragraphs (b), (c), (d), or (e) of this section. (b) For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be self-evident. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the bioavailability or demonstrating the bioequivalence of these drug products. A drug product's in vivo bioavailability or bioequivalence may be considered self-evident based on other data in the application if the product meets one of the following criteria: (1) The drug product: (i) Is a parenteral solution intended solely for administration by injection, or an ophthalmic or otic solution; and (ii) Contains the same active and inactive ingredients in the same concentration as a drug product that is the subject of an approved full new drug application or abbreviated new drug application. (2) The drug product: (i) Is administered by inhalation as a gas, e.g., a medicinal or an inhalation anesthetic; and (ii) Contains an active ingredient in the same dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application. (3) The drug product: (i) Is a solution for application to the skin, an oral solution, elixir, syrup, tincture, a solution for aerosolization or nebulization, a nasal solution, or similar other solubilized form; and (ii) Contains an active d… | |||
| 21:21:5.0.1.1.8.2.1.3 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.23 Basis for measuring in vivo bioavailability or demonstrating bioequivalence. | FDA | [57 FR 17999, Apr. 28, 1992, as amended at 67 FR 77673, Dec. 19, 2002, 81 FR 69658, Oct. 6, 2016] | (a)(1) The in vivo bioavailability of a drug product is measured if the product's rate and extent of absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, urinary excretion rates, or pharmacological effects, do not indicate a significant difference from the reference material's rate and extent of absorption. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. (2) Statistical techniques used must be of sufficient sensitivity to detect differences in rate and extent of absorption that are not attributable to subject variability. (3) A drug product that differs from the reference material in its rate of absorption, but not in its extent of absorption, may be considered to be bioavailable if the difference in the rate of absorption is intentional, is appropriately reflected in the labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug product. (b)(1) Two drug products will be considered bioequivalent drug products if they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alternatives may be equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on chronic use, and are considered medically insignificant for the particular… | |||
| 21:21:5.0.1.1.8.2.1.4 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.24 Types of evidence to measure bioavailability or establish bioequivalence. | FDA | [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July 1, 1992, as amended at 67 FR 77673, Dec. 19, 2002] | (a) Bioavailability may be measured or bioequivalence may be demonstrated by several in vivo and in vitro methods. FDA may require in vivo or in vitro testing, or both, to measure the bioavailability of a drug product or establish the bioequivalence of specific drug products. Information on bioequivalence requirements for specific products is included in the current edition of FDA's publication “Approved Drug Products with Therapeutic Equivalence Evaluations” and any current supplement to the publication. The selection of the method used to meet an in vivo or in vitro testing requirement depends upon the purpose of the study, the analytical methods available, and the nature of the drug product. Applicants shall conduct bioavailability and bioequivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in paragraph (b) of this section. The method used must be capable of measuring bioavailability or establishing bioequivalence, as appropriate, for the product being tested. (b) The following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, are acceptable for determining the bioavailability or bioequivalence of a drug product. (1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is measured as a function of time. This approach is particularly applicable to dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body; or (ii) An in vitro test that has been correlated with and is predictive of human in vivo bioavailability data; or (2) An in vivo test in humans in which the urinary excretion of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time. The intervals at which measurements are taken should ordinarily be as short as possible so that the mea… | |||
| 21:21:5.0.1.1.8.2.1.5 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.25 Guidelines for the conduct of an in vivo bioavailability study. | FDA | [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] | (a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no unnecessary human research should be done. (2) An in vivo bioavailability study is generally done in a normal adult population under standardized conditions. In some situations, an in vivo bioavailability study in humans may preferably and more properly be done in suitable patients. Critically ill patients shall not be included in an in vivo bioavailability study unless the attending physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of an in vivo bioavailability study is determined by the following: (1) The scientific questions to be answered. (2) The nature of the reference material and the dosage form to be tested. (3) The availability of analytical methods. (4) Benefit-risk considerations in regard to testing in humans. (c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in comparison to an appropriate reference material unless some other approach is more appropriate for valid scientific reasons. (d) Previously unmarketed active drug ingredients or therapeutic moieties. (1) An in vivo bioavailability study involving a drug product containing an active drug ingredient or therapeutic moiety that has not been approved for marketing can be used to measure the following pharmacokinetic data: (i) The bioavailability of the formulation proposed for marketing; and (ii) The essential pharmacokinetic characteristics of the active drug ingredient or therapeutic moiety, such as the rate of absorption, the extent of absorption, the half-life of the therapeutic moiety in vivo, and the rate of excretion and/or metabolism. Dose proportionality of the active drug ingredient or the therapeutic moiety needs to be established after single-dose administration and in certain instances after multiple-dose administration. This characterization is a necessary part of the investigation of the drug to support drug labeling. … | |||
| 21:21:5.0.1.1.8.2.1.6 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.26 Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. | FDA | [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] | (a) Basic principles. (1) An in vivo bioavailability or bioequivalence study should be a single-dose comparison of the drug product to be tested and the appropriate reference material conducted in normal adults. (2) The test product and the reference material should be administered to subjects in the fasting state, unless some other approach is more appropriate for valid scientific reasons. (b) Study design. (1) A single-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period. (2) Unless some other approach is appropriate for valid scientific reasons, the drug elimination period should be either: (i) At least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured in the blood or urine; or (ii) At least three times the half-life of decay of the acute pharmacological effect. (c) Collection of blood samples. (1) When comparison of the test product and the reference material is to be based on blood concentration time curves, unless some other approach is more appropriate for valid scientific reasons, blood samples should be taken with sufficient frequency to permit an estimate of both: (i) The peak concentration in the blood of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured; and (ii) The total area under the curve for a time period at least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured. (2) In a study comparing oral dosage forms, the sampling times should be identical. (3) In a study comparing an intravenous dosage form and an oral dosage form, the sampling times should be those needed to describe both: (i) The distribution and elimination phase of the intravenous dosage form; and (ii) The absorption and elimination phase of the oral dosage form. (4) In a study comparing drug delivery systems other than oral or intravenous d… | |||
| 21:21:5.0.1.1.8.2.1.7 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study. | FDA | [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] | (a) Basic principles. (1) In selected circumstances it may be necessary for the test product and the reference material to be compared after repeated administration to determine steady-state levels of the active drug ingredient or therapeutic moiety in the body. (2) The test product and the reference material should be administered to subjects in the fasting or nonfasting state, depending upon the conditions reflected in the proposed labeling of the test product. (3) A multiple-dose study may be required to determine the bioavailability of a drug product in the following circumstances: (i) There is a difference in the rate of absorption but not in the extent of absorption. (ii) There is excessive variability in bioavailability from subject to subject. (iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood resulting from a single dose is too low for accurate determination by the analytical method. (iv) The drug product is an extended release dosage form. (b) Study design. (1) A multiple-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period if steady-state conditions are not achieved. (2) A multiple-dose study is not required to be of crossover design if the study is to establish dose proportionality under a multiple-dose regimen or to establish the pharmacokinetic profile of a new drug product, a new drug delivery system, or an extended release dosage form. (3) If a drug elimination period is required, unless some other approach is more appropriate for valid scientific reasons, the drug elimination period should be either: (i) At least five times the half-life of the active drug ingredient or therapeutic moiety, or its active metabolite(s), measured in the blood or urine; or (ii) At least five times the half-life of decay of the acute pharmacological effect. (c) Achievement of steady-state conditions. Whenever a mu… | |||
| 21:21:5.0.1.1.8.2.1.8 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.28 Correlation of bioavailability with an acute pharmacological effect or clinical evidence. | FDA | [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] | Correlation of in vivo bioavailability data with an acute pharmacological effect or clinical evidence of safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g., in the case of an extended release preparation. | |||
| 21:21:5.0.1.1.8.2.1.9 | 21 | Food and Drugs | I | D | 320 | PART 320—BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS | B | Subpart B—Procedures for Determining the Bioavailability or Bioequivalence of Drug Products | § 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study. | FDA | [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] | (a) The analytical method used in an in vivo bioavailability or bioequivalence study to measure the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, or the method used to measure an acute pharmacological effect shall be demonstrated to be accurate and of sufficient sensitivity to measure, with appropriate precision, the actual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), achieved in the body. (b) When the analytical method is not sensitive enough to measure accurately the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products produced by a single dose of the test product, two or more single doses may be given together to produce higher concentration if the requirements of § 320.31 are met. |
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CREATE TABLE cfr_sections (
section_id TEXT PRIMARY KEY,
title_number INTEGER,
title_name TEXT,
chapter TEXT,
subchapter TEXT,
part_number TEXT,
part_name TEXT,
subpart TEXT,
subpart_name TEXT,
section_number TEXT,
section_heading TEXT,
agency TEXT,
authority TEXT,
source_citation TEXT,
amendment_citations TEXT,
full_text TEXT
);
CREATE INDEX idx_cfr_title ON cfr_sections(title_number);
CREATE INDEX idx_cfr_part ON cfr_sections(part_number);
CREATE INDEX idx_cfr_agency ON cfr_sections(agency);