Regulatory requirements of BIOAVAILABLITY & BIOEQUIVALENCE STUDIES

Regulatory requirements of BIOAVAILABLITY & BIOEQUIVALENCE STUDIES

1. Regulatory requirements of BIOAVAILABLITY & BIOEQUIVALENCE STUDIES 1 Presented by: Megha G. Bhise Department of Regulatory Affairs 1 st Sem M. Pharm Parul University,Vadodara

2. CONTENT Introduction Background Comparison of bioavailability measures in BE studies Requirements of BA/BE Design And Conduct Of Studies Documentation of Bioavailability and Bioequivalence Facilities for conducting bioavailability and bioequivalence studies Maintenance of record of BA/BE studies. 2

3. Introduction This study provides recommendations to sponsors and/or applicants planning to include bioavailability (BA) and bioequivalence (BE) information for drug products in Investigational new drug applications (INDS), New drug applications (NDAS), and NDA supplements. The guidance should be helpful for applicants conducting BA and BE studies during the IND period for an NDA and also for applicants conducting BE studies during the post approval period. FDA's regulations at 21 CFR 320.25 set forth guidelines for in vivo BA studies 3

4. BACKGROUND Bioavailability: Bioavailability Is Defined as ‘‘The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.’’ BA data provide an estimate of the fraction of the drug absorbed, as well as provide information related to the pharmacokinetics of the drug. BA for orally administered drug products can be documented by comparing a systemic exposure profile to that of a suitable reference product. 4 4

5. CONT… Bioequivalence : Bioequivalence means the absence of a significant difference in the rate and extent to which active INGREDIENT in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study (21 CFR 320.1(e)) 5

6. REQUIREMENT OF BA & BE STUDIES For IND/NDAS: To establish equivalence between : early and late clinical trial formulations formulations used in clinical studies and stability studies, if different clinical trial formulations and the to-be-marketed drug product. ANDA for a generic drug product change in components, composition, & manufacturing process change in dosage form (capsules to tablet) 6

7. NDA VS. ANDA REVIEW PROCES NDA Requirements ANDA requirements Chemistry Chemistry Manufacturing Manufacturing Controls Controls Labelling Labelling Testing Testing Preclinical study Clinical study Bioequivalence Bioavailability 7

8. Be for ANDAs Sponsors of ANDAs are required to establish BE between a pharmaceutically equivalent generic drug product and the corresponding listed drug. BE + Pharmaceutical equivalence  Therapeutic equivalence 8

9. Design and conduct of studies According to 21 CFR 320.24 – Invitro & In vivo used to measure product quality and establish BE Pharmaco-kinetic study Pharmacodynamic study Comparative clinical studies In-vitro studies 9

10. CONT… 10

11. 1. Pharmacokinetic Studies General Consideration : PK measures in an accessible biological matrix such as blood, plasma, and/or serum to indicate release of the drug substance from the drug product into the systemic circulation BA and BE frequently rely on PK measures such as AUC to assess extent of systemic exposure and C max and T max to assess rate of systemic absorption. 11

12. CONT… Study design: The study should be designed in such a manner that the formulation effect can be distinguished from other effects. The basic design of an in-vivo bioavailability study is determined by the following: what is the scientific question(s) to be answered. the nature of the reference material and the dosage form to be tested. the availability of analytical methods. 12

13. CONT… Pilot Study A small number of subjects can be carried out before proceeding with a full-scale BA or BE study. It is used to validate analytical methodology, assess PK variability, determine sample size to achieve adequate power, optimize sample collection time intervals. 13

14. Cont ….. Full-scale study : Nonreplicate crossover study designs are recommended for BA and BE studies of immediate-release and modified-release dosage forms Replicate crossover designs are used to allow estimation of within-subject variance for the reference product, or for both the test and reference products, and (2) the subject by formulation interaction variance component. 14

15. CONT… Study Population : BA or BE studies should be 18 years of age or older and capable of giving informed consent. BA and BE studies should be conducted in healthy volunteers if the product can be safely administered to this population. 15

16. CONT… Bioanalytical methodology Sponsors ensure that bioanalytical methods for BA and BE studies be accurate, precise, specific, sensitive, and reproducible. A separate FDA guidance, bioanalytical method validation, is available to assist sponsors in validating bioanalytical methods. 16

17. 2. Pharmacodynamic Study Measurement of effect on a Patho-physiological pr me, after administration of two different products PD studies are not recommended for orally administered drug products when the drug is absorbed into systemic circulation and a PK approach can be used to evaluate BA or BE. PK endpoints are preferred because they are generally the most accurate, sensitive, and reproducible. However, in instances where a PK endpoint is not possible, a well justified PD endpoint can be used to demonstrate BA or BE. 17

18. 3. Comparative clinical studies Clinical endpoints can be used in limited circumstances This study is necessary for both pharmacokinetic & pharmacodynamic properly measurable. For example, for orally administered drug products when the measurement of the active ingredients in an accessible biological fluid (PK approach) or PD approach is not possible because these circumstances do not occur that’s why use of this approach is expected to be rare. 18

19. 4. In vitro studies BA and BE can be evaluated using in vitro approval phases approaches ( e.g , Dissolution/drug-release testing) during the preapproval and post approval phases . For example, orally drugs that are highly soluble and highly permeable, and for Which the drug product is rapidly dissolving, documentation of BE using an in vitro approach may be appropriate based on the BCS system. 19

20. Documentation of ba /be With respect to the conduct of bioequivalence/bioavailability studies following important documents must be maintained: Clinical data: All relevant documents as required to be maintained for compliance with GCP guidelines Details of the analytical method validation including the following: System suitability test Linearity range Lowest limit of quantitation 20

21. CONT… QC sample analysis Stability sample analysis Recovery experiment result Raw data All comments of the chief investigator regarding the data of the study submitted for review. A copy of the final report 21

22. STUDY REPORT The report should include (as a minimum) the following information: a Table of contents Title of the study Names and credentials of responsible investigators Signatures of the principal and other responsible investigators authenticating their respective sections of the report e. Site of the study and facilities used. Site of the study and facilities used Names and batch numbers of the products compared 22

23. CONT… Names and batch numbers of the products compared A signed declaration that this was identical to that intended for marketing. Results of assays and other pharmaceutical tests (e.g., Physical description, dimensions, mean weight, weight uniformity, comparative dissolution) Report of protocol deviations, violations Demographic data of subjects names and addresses of subjects details of and justifications for protocol deviations Details of how pharmacokinetic parameters were calculated. 23

24. FACILITIES FOR CONDUCTING BA/BE STUDIES Legal identity: The organization, conducting the bioequivalence / bioavailability studies must be Legally constituted body with appropriate statutory registrations. 2. Impartiality, confidentiality, independence and integrity: Have managerial staff with the authority and the resources needed to discharge their duties. Have arrangements to ensure that its personnel are free from any commercial, financial and other pressures which might adversely affect the quality of their work. 24

25. Cont... 3. Organisation and management: An investigator who has the overall responsibility to provide of the human subjects. The investigator(s) should possess appropriate medical qualifications and relevant experience for conducting pharmacokinetic studies. The site should have identified adequately qualified and trained personnel to perform the following functions: clinical pharmacological unit (CPU) management. analytical laboratory management data handling and interpretation documentation and report preparation 25

26. D ocumented Standard Operating Procedures 4. D ocumented standard operating procedures A partial list of procedures for which documented standard operating procedures should be available includes: Maintenance of working standards (pure substances) and respective documentation. Withdrawal, storage and handling of biological samples. Maintenance, calibration and validation of instruments. Managing medical as well as non-medical emergency situations 26

27. Cont.. Handling of biological fluids Managing laboratory hazards Disposal procedures for clinical samples and laboratory wastes Documentation of clinical pharmacology unit observations, volunteer data and analytical data . Obtaining informed consent from volunteers Volunteer screening and recruitment and management of ineligible volunteers 27

28. MAINTENANCE OF RECORDS OF BA/BE STUDIES 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 sponsor for at least 2 years after the expiration date of the batch and submitted to CDSCO on request. 28

29. References Https://dineshthakur.Com/wp-content/uploads/2016/06/be-guidelines-draft-ver10-march-16-05.Pdf Https://www.Fda.Gov/regulatory-information/search-fda-guidance-documents/bioavailability-and-bioequivalence-studies-submitted-ndas-or-inds-general-considerations Mastan S, latha TB, ajay S. The basic regulatory considerations and prospects for conducting bioavailability/bioequivalence (BA/BE) studies–an overview. Comp eff res. 2011 mar 22;1:1-25. Chen ML, shah V, patnaik R, adams W, hussain A, conner D, mehta M, malinowski H, lazor J, huang SM, hare D. Bioavailability and bioequivalence: an FDA regulatory overview. Pharmaceutical research. 2001 dec;18(12):1645-50. 29

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