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Assessment of Interchangeable Multisource Medicines BE Study Assessment – Practical Issues

Assessment of Interchangeable Multisource Medicines BE Study Assessment – Practical Issues. Dr. Henrike Potthast. Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009. Guidance Documents. WHO Technical Report Series No. 937 May 2006:

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Assessment of Interchangeable Multisource Medicines BE Study Assessment – Practical Issues

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  1. Assessment of Interchangeable Multisource Medicines BE Study Assessment – Practical Issues Dr. Henrike Potthast Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

  2. Guidance Documents • WHO Technical Report Series No. 937 May 2006: Annex 7: Multisource (generic pharmaceutical products: Guidelines on Registration Requirements to Establish Interchangeability • 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)……………………….and related/others

  3. Some Background Information • drugs are usually administered as dosage forms • the dosage form can affect drug bioavailability • differences in the pharmaceutical formulation can lead to different bioavailabilities • effects of formulation differences apply particularly to oral dosage forms and may be manifest at all stages of the absorption process • in vitro tests provide valuable information but are not necessarily a reliable guide to the bioavailability or therapeutic performance of the product • therapeutic equivalence between like formulations should not be assumed, unless therapeutic equivalence (bioequivalence) has been demonstrated in man; nor should therapeutic equivalence be assumed simply because therapeutic non-equivalence has not been reported (nach D.N. Wade aus ‚Drug Treatment‘, Graeme S. Avery, 1980, Adis Press, Sydney))

  4. 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

  5. Definitions ♦„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

  6. Definitions ♦„…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 Technical Report Series, No. 937, Annex 7]

  7. Definitions ♦„….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?

  8. BE Study Assessment – Practical Issues • 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

  9. BE Study Assessment – Practical IssuesEthical 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 • 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

  10. BE Study Assessment – Practical IssuesEthical 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

  11. BE Study Assessment – Practical IssuesEthical 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

  12. BE Study Assessment – Practical IssuesEthical 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)

  13. BE Study Assessment – Practical IssuesEthical Considerations Approval notification to Investigator as part of study report • 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

  14. BE Study Assessment – Practical IssuesStudy Protocol

  15. BE Study Assessment – Practical IssuesStudy Protocol/Report • „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

  16. BE Study Assessment – Practical IssuesStudy Protocol/Report General Information/Title Page • Title • Protocol Number • Version Number/Date • Sponsor Details • Name, Address, Telephone • Monitor/Medical Personnel  Responsibilities!

  17. BE Study Assessment – Practical IssuesStudy Protocol/Report General Information/Title Page contd. • Investigator Details • Principal Investigator, Medical Doctor • Other Laboratory/Institution Details  Responsibilities!

  18. BE Study Assessment – Practical IssuesStudy Protocol/Report Protocol Development Definition of Responsibilities • Organisation, premises, personnel & QMS • Clinical phase (timely data transfer ensured?) • Bioanalytical phase (timely data transfer ensured?) • Statistics and reporting (timely data transfer ensured?) • Archival

  19. BE Study Assessment – Practical IssuesObjectives Drug substance / Drug products basic knowledge about particularities e.g. • pharmacokinetics(t1/2, peak concentration, time of peak concentration, metabolism, variability?…) • practicability of roughly anticipated measurement period and/or wash-out period(crossover study possible?)

  20. BE Study Assessment – Practical Issues Drug substance / Drug products basic knowledge about particularities e.g. • important side effects(acceptable for healthy volunteers, concomitant medication necessary, acceptable regarding evaluation (e.g. vomiting); acceptable for women with childbearing potential?)

  21. BE Study Assessment – Practical Issues Drug substance / Drug products basic knowledge about particularities e.g. • concept of bioanalytical method available? • plasma concentrations sufficiently quantifiable (LOQ) – e.g. administration of more than one dosage form necessary/possible?

  22. BE Study Assessment – Practical Issues 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)

  23. BE Study Assessment – Practical Issues DrugProducts • batch size • pilot batch? • commercial batch? • not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)

  24. BE Study Assessment – Practical Issues DrugProducts • assay • close to label claim • difference regarding the content of the investigative products (T and R) should preferably not be more than 5 %

  25. BE Study Assessment – Practical IssuesStudy 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

  26. BE Study Assessment – Practical IssuesStudy Subjects • Selection of subjects • males or females or both gender? • “…the sponsor may wish to include both…”(WHO)

  27. BE Study Assessment – Practical IssuesStudy 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; fast and slow metabolizers evenly distributed in parallel group designs)

  28. BE Study Assessment – Practical IssuesStudy 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!

  29. BE Study Assessment – Practical IssuesStudy Subjects • Number of subjects • Required sample size depends on intra-individual variability either known through reasonable literature or by means of a pilot study • “low” variability: ~ 12 – 20 volunteers • “high” variability: ~ 24 – 26 (plus) volunteers

  30. BE Study Assessment – Practical IssuesStudy Subjects • Number of subjects ctd. • Required sample size depends on the expected mean difference between the test and reference formulation • Required sample size depends on the desired significance and power level • For sample size calculation see also 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

  31. BE Study Assessment – Practical IssuesStudy Subjects • Number of subjects • “The number of subjects to be used in the study should be estimated by considering the standards that must be passed. It should be calculated by appropriate methods (…). The number of recruited subjects should always be justified with the sample size calculationprovided in the study protocol. A minimum of 12 subjects is required.” [WHO Technical Report Series, No. 937, Annex 7]

  32. BE Study Assessment – Practical IssuesStudy Subjects • Subject withdrawals • subject must adhere to study requirements… …however … • 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

  33. BE Study Assessment – Practical IssuesStudy Subjects • Subject withdrawals contd… • subject must adhere to study requirements but … • define a time frame regarding vomiting depending also on pharmacokinetics of the drug substance, e.g. volunteers must be withdrawn in case vomiting occurs within 4 h postdose “pre-specify!!”

  34. BE Study Assessment – Practical IssuesStandardisation • 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’)

  35. BE Study Assessment – Practical IssuesStandardisation • Fasted state e.g. • 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

  36. BE Study Assessment – Practical IssuesStandardisation • Standardized fluid and food intake(time, composition, amount) • Prohibition of alcohol • Restriction of xanthins(coffee*, tea, coke, chocolate, chewing gum, grapefruit….) • Standardized posture • Restriction of physical activities … *cave: withdrawal may cause headache

  37. BE Study Assessment – Practical IssuesStandardisation • 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 serve to investigate the „worst case“ scenario

  38. BE Study Assessment – Practical IssuesStudy Samples • Sampling • number of samples • sampling times (Cmax!) • time of sampling (extrapolated AUC max. 20 %) • wash-out-phase (not less than 5 half-lives)  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)

  39. BE Study Assessment – Practical IssuesStudy Samples • Sampling times • appr. 3 – 4 to describe drug “input” • appr. 3 sampling times around peak concentration • appr. 3 – 4 to describe elimination  Minimum!

  40. BE Study Assessment – Practical IssuesStudy Samples • Number of samples • sufficient to “describe” at least 80 % of total AUC • usually ~12– 18 samples (minimum)

  41. BE Study Assessment – Practical IssuesStudy Samples

  42. BE Study Assessment – Practical Issues

  43. BE Study Assessment – Practical Issues Verapamil; BE study; Govi-Verlag 1989

  44. BE Study Assessment – Practical IssuesExceptional Cases! „…Cmax is affected by the sampling points of truncated screening protocol. As isoniazid and pyrazinamide are highly soluble and highly permeable molecules resulting in rapid absorption….Cmax should be carefully evaluated…..AUC was found to be a robust parameter unaffected by sampling points….“ [Panchagnula et al., Pharmacol Res 48 (2003) 383]

  45. BE Study Assessment – Practical IssuesExceptional Cases! Panchagnula et al., Pharmacol Res 48 (2003) 383

  46. BE Study Assessment – Practical IssuesExceptional Cases! Panchagnula et al., Pharmacol Res 48 (2003) 383

  47. BE Study Assessment – Practical IssuesExceptional Cases! „The comparative Spearman‘s correlation analysis on the pharmacokinetic parameters Cmax, AUCt and AUCinf … showed that the 11 time points, namely 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h, were sufficient for demonstration of comparative bioavailability and bioequivalence of INH, RMP, PZA, and EMB, and that a schedule of six time points…..is not adequately reliable for determining the bioavailability and bioequivalence of anti-tuberculosis FDCs.“ [Gabriels et al., Int J Tuberc Lung Dis 11 (2007) 181]

  48. BE Study Assessment – Practical IssuesSampling • Blood withdrawal equipment (consider bioanalytical method) • Preparation of plasma or serum • volume • cooling • anticoagulant • centrifugation • aliquotation • labeling • freezing • transport…

  49. BE Study Assessment – Practical IssuesBioanalytical 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

  50. BE Study Assessment – Practical IssuesCalculations • The protocol should state(-among others-) • the transfer of bioanalytical results for biostatistical calculations • the handling of missing data • the handling of digits

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