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WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, August 2010 BE Study Assessment – Practical Issues

WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, August 2010 BE Study Assessment – Practical Issues Dr. Henrike Potthast (henrike.potthast@bfarm.de). WHO workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August-3. September 2010. Guidance Documents.

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WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, August 2010 BE Study Assessment – Practical Issues

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  1. WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, August 2010 BE Study Assessment – Practical Issues Dr. Henrike Potthast (henrike.potthast@bfarm.de) WHO workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August-3. September 2010

  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 Rev.1 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 containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy .“ [section 1.1 of the revised EU guidance on 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 Issues What do we need to know? How to ensure bioequivalence?

  10. 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” evaluation

  11. 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

  12. 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

  13. BE Study Assessment – Practical IssuesEthical Considerations Documents that should be available for the IRB • Protocol (signed at least by the principal investigator) • Patient Information Sheet/Consent Form • Investigator´s Brochure • Subject recruitement procedures (e. g. advertisements)

  14. BE Study Assessment – Practical IssuesEthical Considerations Approval notification to be available in the study report • Timely written approval • Identification of study (title, protocol number, version, investigator, site) • Specifification of 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

  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 Protocol Report

  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 or is there a need for a study in patients?, 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 acceptable/necessary/possible?

  22. BE Study Assessment – Practical Issues DrugProducts • Availability • Certification • Content/Potency • (comparative) 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) - this is of particular importance -

  24. BE Study Assessment – Practical Issues DrugProducts (WHOTechn. Rep. Series No. 937 May 2006 Annex 7, sect. 6.5.1) • “…Batch-control results of the multisource product, and the lot numbers and expiry dates of both multisource and comparator products should be stated…. • It is recommended that potency and in vitro dissolution characteristics of the multisource and the comparator pharmaceutical products be ascertained prior to performance of an equivalence study….”

  25. BE Study Assessment – Practical Issues DrugProducts • assay • close to label claim • difference regarding the content of the investigative products (T and R) should preferably be not more than 5 % - (“dose correction”?!)

  26. BE Study Assessment – Practical Issues DrugProducts • Dose to be investigated (WHOTechn. Rep. Series No. 937 May 2006 Annex 7, sect. 6.6.1) “In bioequivalence studies the molar equivalent dose of multisource and comparator product must be used.”

  27. BE Study Assessment – Practical Issues DrugProducts • Dose to be investigated ctd.(WHOTechn. Rep. Series No. 937 May 2006 Annex 7, sect. 6.6.1) – product series • “Generally the marketed strength with the greatest sensitivity to bioequivalence assessment should be administered as a single unit. This will usually be the highest marketed strength. A higher dose (i.e. more than one dosage unit) may be employed when analytical difficulties exist. In this case the total single dose should not exceed the maximal daily dose of the dosage regimen. Alternatively, the application of area under the curve (AUC) truncated to 3 × median tmax of the comparator formulation would avoid problems of lack of assay sensitivity in many cases. In certain cases a study performed with a lower strength can be considered acceptable if this lower strength is chosen for reasons of safety.”

  28. BE Study Assessment – Practical Issues DrugProducts • Dose to be investigated ctd.– product series • Cave: – if AUC increases less than proportional with dose then the lower dose may be most sensitive -

  29. 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

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

  31. 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)

  32. BE Study Assessment – Practical IssuesStudy Subjects • Selection of subjects ctd. (WHOTechn. Rep. Series No. 937, sect. 6.3.5) • “Phenotyping for metabolizing activity can be of importance for studies with high-clearance drugs that are metabolized by enzymes that are subject to genetic polymorphism, e.g. propranolol. In such cases, slow metabolizers will have a higher bioavailability of the parent drug, while the bioavailability of possible active metabolites will be lower. Phenotyping of subjects can be considered for studies of drugs that show phenotype-linked metabolism and for which a parallel group design is to be used… Phenotyping could also be important for safety reasons, determination of samplingtimes and wash-out periods in cross-over design studies.”

  33. BE Study Assessment – Practical IssuesStudy Subjects • Selection of subjects • description of volunteers;smoker, vegetarian, phenotyping…. EU: healthy, BMI; FDA: both sexes, > 18y; WHO: 18-55y) • verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure…) • number of volunteers depending on variability (at least 12) • randomisation objective: minimising interindividual variability in order to detect possible product differences!

  34. 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

  35. 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

  36. BE Study Assessment – Practical IssuesStudy Subjects • Number of subjects ctd • “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]

  37. 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 • comprehensive reporting in the study report

  38. 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!!”

  39. 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’)

  40. 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

  41. 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

  42. 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 and formulation robustness

  43. BE Study Assessment – Practical IssuesStandardisation • Fed state ctd: (WHO Technical Report Series, No. 937, Annex 7, sect. 6.4) „Some medicines are normally given with food to reduce gastrointestinal side-effects; in certain cases coadministration with food increases bioavailability of orally administered preparations. If the labelling states that the pharmaceutical product should be taken with food then a fed study should be used to assess bioequivalence. Fed state studies are also required in bioequivalence studies of modified release formulations. In these cases the objective is to select a meal that will challenge the robustness of the new multisource formulation to prandial effects on bioavailability (see 6.2.4). The test meal selected should take account of local custom and diet and should be consumed within 20 minutes. The product should be administered according to the protocol and within 30 minutes after the meal has been eaten.“

  44. 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‘!

  45. 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!

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

  47. BE Study Assessment – Practical IssuesStudy Samples • WHO Technical Report Series 937 Annex 7 sect. 6.6.2 “Blood samples should be taken at a frequency sufficient for assessing Cmax, AUC and other parameters. Sampling points should include a pre-dose sample, at least 1–2 points before Cmax, 2 points around Cmax and 3–4 points during the elimination phase. Consequently at least seven sampling points will be necessary for estimation of the required pharmacokinetic parameters. For most medicines the number of samples necessary will be higher to compensate for between-subject differences in absorption and elimination rate and thus enable accurate determination of the maximum concentration of the API in the blood (Cmax) and terminal elimination rate constant in all subjects..”

  48. BE Study Assessment – Practical IssuesStudy Samples • WHO Technical Report Series 937 Annex 7 sect. 6.6.2 “Generally, sampling should continue for long enough to ensure that 80% of the AUC (0→ infinity) can be accrued, but it is not necessary to sample for more than 72 hours. The exact duration of sample collection depends on the nature of the API and the input function from the administered dosage form (see also 6.11.4).”

  49. BE Study Assessment – Practical IssuesStudy Samples • WHO Technical Report Series 937 Annex 7 sect. 6.2.2 “For both cross-over and parallel-design studies, sample collection time should be adequate to ensure completion of gastrointestinal transit (approximately 2–3 days) of the pharmaceutical product and absorption of the API. Blood sampling up to 72 hours following administration should be carried out, unless shorter periods can be justified.”

  50. BE Study Assessment – Practical IssuesStudy Samples

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