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World Health Organization Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence Planning a BE Study Kiev, October 3 – 7, 2005 Dr. H. Potthast (h.potthast@bfarm.de). Guidance Documents. EU “ Note for Guidance on the Investigation of

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World Health Organization Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence


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    1. World Health Organization Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence Planning a BE Study Kiev, October 3 – 7, 2005Dr. H. Potthast (h.potthast@bfarm.de)

    2. Guidance Documents • 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 • related guidances and current scientific discussion

    3. 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

    4. 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

    5. Definitions ♦„A generic medicinal product shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.“ [new EU Directive 2004/27/EC: Art. 10.1]

    6. 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?

    7. BE Objectives • 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

    8. Choice of Design • Single-dose Studies  usually for IR drug products • Multiple-dose/steady-state Studies • usually for MR drug products in addition to single-dose studies • dose/time dependent pharmacokinetics (mainly BA studies!) • possible analytical problems • variability issues

    9. Study Protocol

    10. Study 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

    11. Study Protocol General Information/Title Page • Title • Protocol Number • Version Number/Date • Sponsor Details • Name, Address, Telephone • Monitor/Medical Personnel • Investigator Details • Principal Investigation, Medical Doctor • Other Laboratory/Institution Details  Responsibilities!

    12. Ethical 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

    13. Ethical Considerations Composition requirements ICH 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

    14. Ethical Considerations 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

    15. Ethical 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)

    16. Ethical 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

    17. Study Protocol Protocol Development Definition of Responsibilities • Organisation, premises, personnel & QMS • Clinical phase • Bioanalytical phase • Statistics and reporting • Archival

    18. Protocol Development Drug substance / Drug products Knowledge of Particularities e.g. • pharmacokinetics (t1/2, peak concentration, metabolism…) • important side effects (acceptable for healthy volunteers?) • practicability of roughly anticipated measurement period and/or wash-out period (crossover study possible?) • concept of bioanalytical method available? • plasma concentrations sufficiently quantifiable (administration of more than one dosage form necessary?)

    19. Protocol Development Drug Products • 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)

    20. Study 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!

    21. Study Subjects • Selection of subjects • Safe contraception for women (cave: interferences of contraceptives with investigative drug excluded?) • Phenotyping of volunteers (cave: possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation)

    22. Study Subjects • Selection of subjects • participation of healthy volunteers (“in vivo model”) • reasonable inclusion and exclusion criteria (protocol and CRFs) • comprehensive verbal and written information • volunteers´ insurance • reimbursement

    23. Study 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 volunteers

    24. Study 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

    25. Study Subjects • Subject withdrawals • subject must adhere to study requirements but … • they are free to break of at any time • definition of “drop-outs” in the protocol (reason, reimbursement policy, handling of data, follow-up…) • concomitant medication • reporting

    26. Study Design • Crossover-design “latin square” / balanced / randomized • Intra-individual comparison! • Parallel group design • Replicate design

    27. Standardisation • 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’)

    28. Standardisation • Standardised 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

    29. Standardisation • 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 xanthine-free liquid • Light standardized meal not before ~4 h post-dose

    30. Standardisation • 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

    31. Study Samples • Sampling • number of samples • sampling times (Cmax!) • time of sampling (extrapolated AUC max. 20 %) • wash-out-phase (3 – 4 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)

    32. Study Samples • Number of samples • sufficient to “describe” at least 80 % of total AUC • usually ~12 – 18 samples

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

    34. Study Samples • Wash-out-phase • must be long enough to avoid residual concentrations • closely related to the limit of quantitation • metabolites may be considered

    35. Sampling • Blood withdrawal equipment (consider bioanalytical method) • Preparation of plasma or serum • cooling • centrifugation • aliquotation • labeling • freezing • transport…

    36. Bioanalytical 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

    37. Calculations • The protocol should state (-among others-) • the transfer of bioanalytical results for biostatistical calculations • the handling of missing data • the handling of digits

    38. Calculations • The protocol should state (-among others-) • calculation procedure/methods • primary characteristics • possible consideration of differences of drug content • acceptance ranges

    39. Adverse Events • Definitions and handling/information • Evaluation of seriousness • Evaluation of relation to investigative drugs • Treatment (cave: concomitant drug intake should be testet a priori for possible analytical interferences)

    40. Study protocol ?ANY MORE QUESTIONS?