FDB FOOD AND DRUGS BOARD G H A N A GUIDELINES FOR CONDUCTING BIOEQUIVALENCE STUDIES

Transcription

1 FDB FOOD AND DRUGS BOARD G H A N A GUIDELINES FOR CONDUCTING BIOEQUIVALENCE STUDIES 1 SCOPE In pursuance of section 47 of the Food and Drugs Law 1992, P.N.D.C.L 305B, as amended by Act 523, 1996, these Guidelines are made to ensure that pharmaceutically equivalent products are therapeutically equivalent in order to be considered interchangeable. 2 DEFINITION OF TERMS 2.1 In these Guidelines, unless the context otherwise states: a) Board means the Food and Drugs Board b) bioavailability means the percentage of a drug contained in a product that enters the systemic circulation in an unchanged form after administration of the product. c) bioequivalence means that two proprietary preparations of a drug, when administered in the same dose and by the same route, will have the same bioavailability, duration of action and efficacy. d) pharmaceutically equivalent products means two proprietary products that contain the same amount of the same active substance(s) in the same dosage form which meet the same comparable standards and are indicated to be administered by the same route. e) therapeutically equivalent products means two proprietary products that have the same or no statistically significant differences in clinical response or activity. f) OTC means an over-the-counter medicinal product that can be dispensed without a prescription. g) lead market brand means a branded product which has been determined by criteria including, but not limited to, the following to be the lead brand; sales volume

2 safety profile number of prescriptions expert opinion h) reference product means the innovator or lead market brand. 3 REQUIREMENTS 3.1 General Requirements a) Test methods acceptable to the Board in assessing bioequivalence shall include, but not be limited to, the following: i. Comparative bioequivalence studies in which the active drug substance or one or more metabolites is measured in an accessible biological fluid such as plasma, blood or urine (where applicable). ii. Comparative pharmacodynamic studies in humans. iii. Comparative clinical trials. iv. In vitro bioequivalence studies. b) Bio-equivalence studies shall be carried out in accordance with the guidelines for conducting clinical trials with strict adherence to Good Clinical Practice (GCP) and Good Laboratory Practices (GLP) as specified in the Helsinki Declaration. (Refer Food and Drug Board Guidelines for Conducting Clinical Trials of Allopathic Drugs and World Medical Association Declaration of Helsinki -Ethical Principles for Medical Research Involving Human Subjects c) A study report shall be submitted to include, but not be limited to, the following: i. Approval issued by a recognised Independent Ethics Committee or Institutional Review Board. ii. Informed consent forms for volunteers used for the study iii. Titles and Curriculum Vitae of medical and scientific staff iv. Demography of volunteers used for the study v. Bio-analytical method validation reports vi. Results of analysis Total Exposure or area under the concentration-time curve (AUCt, AUC 0- ) Peak exposure (C max ) Time to peak exposure (T max ) Lag Time (T lag ) for modified release products if present Terminal elimination half-life Pharmacokinetic results and tabulation for individual subjects and graphical presentation

3 Other relevant pharmacokinetic parameters 3.2 Special Requirements In vivo Bioequivalence Studies a) For certain drugs and dosage forms, in vivo documentation of bioequivalence or report of a comparative pharmacodynamic study or comparative clinical trial shall be submitted to the Board. b) This shall include, but not be limited to: i. Oral immediate release pharmaceutical products with systemic action when one or more of the following criteria apply: Indicated for a serious condition requiring assured therapeutic response Narrow therapeutic window and or narrow safety margin or step dose-response curve. Pharmacokinetics complicated by variable or incomplete absorption or absorption window, non-linear pharmacokinetics, pre-systemic elimination and / or high first pass metabolism greater than 70% Unfavourable physicochemical properties such as low solubility, instability, poor permeability, unfavourable ionisation; Documented evidence for bioavailability problems related to the drug or drugs similar in chemical structure or formulations Where a high ratio of excipients to active ingredients exists. ii. iii. iv. Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption, such as transdermal patches and suppositories Sustained or otherwise modified release pharmaceutical designed to act by systemic absorption. Fixed OTC combination products with systemic action. v. Non-soluble pharmaceutical products which are for non-systemic use, such as oral, nasal, ocular, dermal, rectal and vaginal applications.

4 c) This does not exclude the potential need for drug concentration measurements in order to assess unintended partial absorption. d) The number of volunteers in all cases should not be less than 24 (twentyfour) In-vitro Bioequivalence Studies a) In certain circumstances, bioequivalence may be assessed by the use of in-vitro dissolution testing. b) These include, but are not limited to: i. Different strengths of a generic product, when the pharmaceutical products are manufactured by the same manufacturer at the same manufacturing site where; The qualitative composition between the two strengths is essentially the same. An in vivo or in vitro equivalence study has been performed on at least one of the strengths of the formulation, preferably the highest strength, and the ratio of the strengths of excipients are the same. In cases where systemic availability pharmacokinetics have been shown to be linear over the therapeutic dose range. ii. The drug has a parameter for assessing bioequivalence in an official monograph recognized by the Board.

5 3.2.3 Situations in which Bioequivalence Studies are not Required a) When the generic product is to be administered parenterally as an aqueous solution containing the same active substance(s) in the same concentration and the same excipients in comparable concentrations. b) When the generic products are solutions for oral use, contain the active substance in the same concentration, and do not contain an excipient that is known or suspected to affect gastrointestinal transit or absorption of the active substance. c) When the generic product is a gas. d) When the generic product is a powder for reconstitution as a solution and the solution meets criteria (b) above. e) When the generic product is an otic, ophthalmic or other topical product, prepared as an aqueous solution and contains the same active substance(s) in the same concentration and similar excipients in comparable concentrations. f) Special in vitro testing shall be required to document comparable device performance of the generic inhalation products, when the generic product is an inhalation product or nasal spray, tested to be administered with or without essentially the same device and prepared as an aqueous solution, and contains the same active substance(s) in the same concentration and similar excipients in concentrations that are comparable. g) For all products mentioned above, it is incumbent upon the applicant to demonstrate that the excipients in the generic product are internationally acceptable and approved, and incomparable concentrations as those in the reference product. h) In the event that information about the reference product or lead market brand cannot be provided by the applicant, and the drug regulatory authority does not have access to this data, a full Clinical Trial study shall be required as specified in the guidelines for conducting clinical trials (Refer to FDB Guidelines for Conducting Clinical Trials of Allopathic Drugs )