[Code of Federal Regulations] [Title 21 Volume 5] [Revised as of April 1, 2003] From the U.S. Government Printing Office via GPO Access [CITE: 21CFR320.25] [Page 184-186] TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS--Table of Contents Subpart B--Procedures for Determining the Bioavailability or Bioequivalence of Drug Products Sec. 320.25 Guidelines for the conduct of an in vivo bioavailability study. (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. (2) The reference material in such a bioavailability study should be a solution or suspension containing the same quantity of the active drug ingredient or therapeutic moiety as the formulation proposed for marketing. (3) The reference material should be administered by the same route as the [[Page 185]] formulation proposed for marketing unless an alternative or additional route is necessary to answer the scientific question under study. For example, in the case of an active drug ingredient or therapeutic moiety that is poorly absorbed after oral administration, it may be necessary to compare the oral dosage form proposed for marketing with the active drug ingredient or therapeutic moiety administered in solution both orally and intravenously. (e) New formulations of active drug ingredients or therapeutic moieties approved for marketing. (1) An in vivo bioavailability study involving a drug product that is a new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing can be used to: (i) Measure the bioavailability of the new formulation, new dosage form, or new salt or ester relative to an appropriate reference material; and (ii) Define the pharmacokinetic parameters of the new formulation, new dosage form, or new salt or ester to establish dosage recommendation. (2) The selection of the reference material(s) in such a bioavailability study depends upon the scientific questions to be answered, the data needed to establish comparability to a currently marketed drug product, and the data needed to establish dosage recommendations. (3) The reference material should be taken from a current batch of a drug product that is the subject of an approved new drug application and that contains the same active drug ingredient or therapeutic moiety, if the new formulation, new dosage form, or new salt or ester is intended to be comparable to or to meet any comparative labeling claims made in relation to the drug product that is the subject of an approved new drug application. (f) Extended release formulations. (1) The purpose of an in vivo bioavailability study involving a drug product for which a extended release claim is made is to determine if all of the following conditions are met: (i) The drug product meets the extended release claims made for it. (ii) The bioavailability profile established for the drug product rules out the occurrence of any dose dumping. (iii) The drug product's steady-state performance is equivalent to a currently marketed nonextended release or extended release drug product that contains the same active drug ingredient or therapeutic moiety and that is subject to an approved full new drug application. (iv) The drug product's formulation provides consistent pharmacokinetic performance between individual dosage units. (2) The reference material(s) for such a bioavailability study shall be chosen to permit an appropriate scientific evaluation of the extended release claims made for the drug product. The reference material shall be one of the following or any combination thereof: (i) A solution or suspension of the active drug ingredient or therapeutic moiety. (ii) A currently marketed noncontrolled release drug product containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labeling of the noncontrolled release drug product. (iii) A currently marketed extended release drug product subject to an approved full new drug application containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labeling proposed for the extended release drug product. (iv) A reference material other than one set forth in paragraph (f)(2) (i), (ii) or (iii) of this section that is appropriate for valid scientific reasons. (g) Combination drug products. (1) Generally, the purpose of an in vivo bioavailability study involving a combination drug product is to determine if the rate and extent of absorption of each active drug ingredient or therapeutic moiety in the combination drug product is equivalent to the rate and extent of absorption of each active drug ingredient or therapeutic moiety administered concurrently in separate single-ingredient preparations. (2) The reference material in such a bioavailability study should be two or [[Page 186]] more currently marketed, single-ingredient drug products each of which contains one of the active drug ingredients or therapeutic moieties in the combination drug product. The Food and Drug Administration may, for valid scientific reasons, specify that the reference material shall be a combination drug product that is the subject of an approved new drug application. (3) The Food and Drug Administration may permit a bioavailability study involving a combination drug product to determine the rate and extent of absorption of selected, but not all, active drug ingredients or therapeutic moieties in the combination drug product. The Food and Drug Administration may permit this determination if the pharmacokinetics and the interactions of the active drug ingredients or therapeutic moieties in the combination drug product are well known and the therapeutic activity of the combination drug product is generally recognized to reside in only one of the active drug ingredients or therapeutic moieties, e.g., ampicillin in an ampicillin-probenecid combination drug product. (h) Use of a placebo as the reference material. Where appropriate or where necessary to demonstrate the sensitivity of the test, the reference material in a bioavailability study may be a placebo if: (1) The study measures the therapeutic or acute pharmacological effect of the active drug ingredient or therapeutic moiety; or (2) The study is a clinical trial to establish the safety and effectiveness of the drug product. (i) Standards for test drug product and reference material. (1) Both the drug product to be tested and the reference material, if it is another drug product, shall be shown to meet all compendial or other applicable standards of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and dissolution rates. (2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same conditions as those used for full-scale production. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002]