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Planning a BE Study

Planning a BE Study. Training Program on Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence Jiaxing, Zhejiang, China 5 – 9 November 2007 Dr. Henrike Potthast (h.potthast@bfarm.de) temporary advisor to WHO. Guidance Documents.

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Planning a BE Study

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  1. Planning a BE Study Training Program on Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence Jiaxing, Zhejiang, China 5 – 9 November 2007 Dr. Henrike Potthast (h.potthast@bfarm.de) temporary advisor to WHO

  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

  3. Some Background Information CTD 5.3 Clinical Study Reports 5.3.1 Biopharmaceutic Studies (bioavailability and bioequivalence; “what does the product do to the drug substance”) 5.3.2. + 5.3.3 Human Pharmacokinetic Studies (in situ and in vivo; „what does the body do to the drug substance”) 5.3.4 Human Pharmacodynamic Studies („what does the drug substance do to the body“) 5.3.5 Efficacy and Safety Studies

  4. Planning a BE Study 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))

  5. 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

  6. 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

  7. 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]

  8. 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]

  9. 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?

  10. 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

  11. 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 • 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

  12. 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

  13. 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

  14. 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)

  15. Planning a BE StudyEthical 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

  16. Planning a BE StudyStudy Protocol

  17. 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

  18. Planning a BE StudyStudy Protocol General Information/Title Page • Title • Protocol Number • Version Number/Date • Sponsor Details • Name, Address, Telephone • Monitor/Medical Personnel  Responsibilities!

  19. Planning a BE StudyStudy Protocol General Information/Title Page contd. • Investigator Details • Principal Investigator, Medical Doctor • Other Laboratory/Institution Details  Responsibilities!

  20. Planning a BE StudyStudy Protocol 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

  21. Planning a BE StudyProtocol Development 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?)

  22. Planning a BE StudyProtocol Development 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?)

  23. 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) – e.g. administration of more than one dosage form necessary/possible?

  24. 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)

  25. Planning a BE StudyProtocol Development DrugProducts • batch size • pilot batch? • commercial batch? • not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)

  26. Planning a BE StudyProtocol Development DrugProducts • assay • close to label claim • difference regarding the content of the investigative products (T and R) should preferably not be more than 5 %

  27. 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

  28. Planning a BE StudyStudy Subjects • Selection of subjects • males or females or both gender? • “…the sponsor may wish to include both…”(WHO)

  29. 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; fast and slow metabolizers evenly distributed in parallel group designs)

  30. 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!

  31. Planning a BE StudyStudy 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

  32. 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 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

  33. Planning a BE StudyStudy Subjects • Number of subjects ctd. • Required sample size depends on the desired significance and power level • 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 …)

  34. Planning a BE StudyStudy 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 – working document on multisource (generic) pharmaceutical products (QAS/04.093)

  35. Planning a BE StudyStudy 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

  36. Planning a BE StudyStudy 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!!”

  37. Planning a BE StudyStudy Design • Randomization to a Crossover-design “latin square” / balanced / randomized • Intra-individual comparison! • Parallel group design • Replicate design

  38. Planning a BE StudyStudy Design • others e.g., • Parallel group design • Replicate design

  39. 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’)

  40. Planning a BE StudyStandardisation • 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. Planning a BE StudyStandardisation • 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. 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 serve to investigate the „worst case“ scenario

  43. Planning a BE StudyStudy 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)

  44. 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!

  45. Planning a BE StudyStudy Samples • Number of samples • sufficient to “describe” at least 80 % of total AUC • usually ~12– 18 samples (minimum)

  46. Planning a BE StudyStudy Samples

  47. Planning a BE Study

  48. Planning a BE Study Verapamil; BE study; Govi-Verlag 1989

  49. Planning a BE StudyExceptional 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]

  50. Planning a BE StudyExceptional Cases! Panchagnula et al., Pharmacol Res 48 (2003) 383

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