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Planning a BE Study

Planning a BE Study. Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO. Guidance Documents.

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Planning a BE Study

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  1. Planning a BE Study Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  2. Guidance Documents • WHO Working Document Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability November 2005 • EU “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98 and related guidances and documents (www.emea.eu.int/pdfs/human/ewp ) • FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000) • Canadian Guidance for Industry: “Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations used for systemic effects.” (1992)……………………….an related/others Pt WHO-consultantThe BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  3. Planning a BE Study Definitions • Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!) • Bioequivalence – equivalent bioavailability within pre-set acceptance ranges • Pharmaceutical equivalence Bioequivalence • Bioequivalence Therapeutic equivalence Pt WHO-consultantThe BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  4. Planning a BE StudyDefinitions ♦„Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives AND if their bioavailabilities after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same.“ [section 2.4 of the EU guidance on BA and BE]  possible surrogate for full clinical/toxicological documentation The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  5. Planning a BE StudyDefinitions ♦Bioequivalence is „…the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.“ [FDA Guidance for Industry Bioavailability and Bioequivalence Studies for orally administered Drug Products-General Considerations March 2003] The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  6. Planning a BE StudyDefinitions ♦„…Bioequivalence focuses on the equivalence of release of the active pharmaceutical ingredient from the pharmaceutical product and its subsequent absorption into the systemic circulation.“ [WHO Working Document Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability November 2005] The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  7. Planning a BE StudyDefinitions ♦ „….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.“ [Faassen et al. Clin Pharmacokinet 43 (2004)1117]  what does the product do to the drug substance? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  8. Planning a BE study • Bioequivalence Studies • in vivo comparison by means of volunteers serving as “in vivo dissolution model” • ‘biological quality control’  comparison of product characteristics in order to ensure therapeutic equivalence The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  9. Planning a BE StudyEthical Considerations IEC / IRB: ICH Definition • An independent body of medical, scientific and non-scientific members • Responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, • Among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects; • Independent “Risk-benefit” evalution The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  10. Planning a BE StudyEthical Considerations Composition requirementsICH GCP • At least 5 members • At least one member whose primary area of interest is a non-scientific area • At least one member who is independent of the trial site • Members without conflicting interest Only those members independent of the investigator and the sponsor should review on a trial-related matter The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  11. Planning a BE StudyEthical considerations e.g. additional US FDA requirement for IRB composition: • Diverse backgrounds (race, gender, cultural, qualification) • Not entirely one gender • Special expertise may be invited but without voting rights The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  12. Planning a BE StudyEthical Considerations Required documents • Protocol (signed at least by the principal investigator) • Patient Information Sheet/Consent Form • Investigator´s Brochure • Subject recruitement procedures (e. g. advertisements) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  13. Planning a BE StudyEthical Considerations Approval notification to Investigator • Timely written approval • Identification of study (title, protocol number, version, investigator, site) • Specify all items reviewed • Date & place of review • Trial/study related decisions • Reasons for modifications & disapprovals Minimum information required by ICH-GCP: • Date of the meeting • Documents reviewed (versions & dates) • List of members The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  14. Planning a BE StudyStudy Protocol The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  15. Planning a BE StudyStudy Protocol • „A document that describes the objective(s), design, methodology, statistical consideration and organisation of a trial. It usually gives the background and rationale of the trial …“ Ref.: ICH GCP Guidance The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  16. Planning a BE StudyStudy Protocol General Information/Title Page • Title • Protocol Number • Version Number/Date • Sponsor Details • Name, Address, Telephone • Monitor/Medical Personnel • Investigator Details • Principal Investigator, Medical Doctor • Other Laboratory/Institution Details  Responsibilities! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  17. Planning a BE StudyStudy Protocol Protocol Development Definition of Responsibilities • Organisation, premises, personnel & QMS • Clinical phase • Bioanalytical phase • Statistics and reporting • Archival The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  18. Planning a BE StudyProtocol Development Drug substance / Drug products basic knowledge about particularities e.g. • pharmacokinetics (t1/2, peak concentration, metabolism…) • practicability of roughly anticipated measurement period and/or wash-out period (crossover study possible?) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  19. Planning a BE StudyProtocol Development Drug substance / Drug products basic knowledge about particularities e.g. • important side effects (acceptable for healthy volunteers?) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  20. Planning a BE StudyProtocol Development Drug substance / Drug products basic knowledge about particularities e.g. • concept of bioanalytical method available? • plasma concentrations sufficiently quantifiable (LOQ) (administration of more than one dosage form necessary/possible?) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  21. Planning a BE StudyProtocol Development DrugProducts • Availability • Certification • Content • In vitro dissolution • Preparation of investigative products per volunteer acc. to GMP • Protocol amendment for product details frequently necessary (e. g. labeling) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  22. Planning a BE StudyStudy Subjects • Selection of subjects • description of volunteers;smoker, vegetarian, phenotyping…. • verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure…) • number of volunteers depending on variability; at least 12(EU: healthy, 18-55y; FDA: both sexes, > 18y) • randomisation objective: minimising interindividual variability in order to detect product differences! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  23. Planning a BE StudyStudy Subjects • Selection of subjects • Safe contraception for women (cave: interferences of contraceptives with investigative drug excluded?) • Phenotyping of volunteers (cave: possible side effects with e.g. “poor metabolisers” may cause drop-outs; variability reduction/explanation) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  24. Planning a BE StudyStudy Subjects • Selection of subjects • participation of healthy volunteers (“in vivo model”) • reasonable inclusion and exclusion criteria (protocol and CRFs) • comprehensive verbal and written information and informed consent • volunteers´ insurance • reimbursement The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  25. Planning a BE StudyStudy Subjects • Number of subjects • Required sample size depends on variability either known through reasonable literature or by means of a pilot study • “low” variability: ~ 12 – 20 volunteers • “high” variability: ~ 24 – 26 (plus) volunteers The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  26. Planning a BE StudyStudy Subjects • Number of subjects ctd. • Required sample size depends on the expected mean difference between the test and reference formulation • For sample size calculation see literature data (e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41; J Biopharm Stat 13 (2003) 529; Stat Med 18 (1999) 93 …) • Consideration of possible withdrawals The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  27. Planning a BE StudyStudy Subjects • Subject withdrawals • subject must adhere to study requirements but … • they are free to break off at any time • definition of “drop-outs” in the protocol (reason, reimbursement policy, handling of data, follow-up…) • concomitant medication • reporting The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  28. Planning a BE StudyStudy Design • Crossover-design “latin square” / balanced / randomized • Intra-individual comparison! • Parallel group design • Replicate design The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  29. Planning a BE StudyStandardisation • Procedure of drug intake • time of administration (fasted or fed state) • liquid volume • traceability of administrations • cave: e.g. granules, suspensions liquid formulations! (require ‘method sheet’) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  30. Planning a BE StudyStandardisation • Standardized fluid and food intake(time, composition, amount) • Prohibition of alcohol • Restriction of xanthins(coffee*, coke, chocolate, chewing gum, grapefruit….) • Standardized posture • Restriction of physical activities … *cave: withdrawal may cause headache The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  31. Planning a BE StudyStandardisation • Fasted state • Confinement of subjects at least 10 h prior to drug administration • Last food intake ~10 h prior to drug intake • No food or fluids ~2 h prior to drug intake • Drug administration with ~150-200 ml (e.g.) water • Light standardized meal not before ~4 h post-dose The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  32. Planning a BE StudyStandardisation • Fed state • Define time of drug administration and food intake, (e. g. drug intake within 30 min. before, immediately before or after the standardised meal) • High fat meal may serves to investigate the „worst case“ scenario The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  33. Planning a BE StudyStudy Samples • Sampling • number of samples • sampling times (Cmax!) • time of sampling (extrapolated AUC max. 20 %) • wash-out-phase (4 – 5 half-lifes)  knowledge of basic pharmacokinetics of the particular drug substance is inevitable! objective: characterisation of ‚drug input‘! (see e.g. sect. 3.1 of the EU guidance 1401/98) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  34. Planning a BE StudyStudy Samples • Number of samples • sufficient to “describe” at least 80 % of total AUC • usually ~12– 18 samples (minimum) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  35. Planning a BE StudyStudy Samples • Sampling times • appr. 3 – 4 to describe drug “input” • appr. 3 sampling times around peak concentration • appr. 3 – 4 to describe elimination  Minimum! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  36. Planning a BE StudyStudy Samples • Wash-out-phase • must be long enough to avoid residual concentrations • closely related to the limit of quantitation • metabolites may be considered The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  37. The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  38. Planning a BE StudySampling • Blood withdrawal equipment (consider bioanalytical method) • Preparation of plasma or serum • cooling • centrifugation • aliquotation • labeling • freezing • transport… The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  39. Planning a BE StudyBioanalytical Method • The protocol should state • the bioanalytical method/detection • the limit of quantitation (1/10 of the expected peak concentration should be measurable) • the validation concept • whether metabolites are to be considered The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  40. Planning a BE StudyCalculations • The protocol should state (-among others-) • the transfer of bioanalytical results for biostatistical calculations • the handling of missing data • the handling of digits The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  41. Planning a BE StudyCalculations • The protocol should state (-among others-) • calculation procedure/methods • primary characteristics (e.g. AUC, Cmax…) • possible consideration of differences of drug content • acceptance ranges The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  42. Planning a BE StudyModified Release Products • The protocol should state/ensure/consider • direct switching vs. wash-out • primary characteristics (e.g. AUCtau, Cmax, Cmin…) • consideration of fluctuation (e.g. Ptf…) • compare Cmin to ensure steady-state The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  43. Planning a BE Study - Adverse Events • Definitions and handling/information • Evaluation of seriousness • Evaluation of relation to investigative drugs • Treatment (cave: concomitant drug intake should be tested ‘a priori’ for possible analytical interferences) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  44. Planning a BE Study-Results… The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  45. Planning a BE Study THANK YOU FOR YOUR ATTENTION The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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