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planning a BE study

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Title: planning a BE study Subject: BE Author: potthast Last modified by: Smid, Milan Created Date: 8/6/2007 2:30:51 PM Document presentation format – PowerPoint PPT presentation

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Title: planning a BE study


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/toxicologic
    al 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 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
  • 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 Issues 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

11
BE Study Assessment Practical Issues Ethical
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 Issues Ethical
Considerations
  • Required documents
  • Protocol (signed at least by the principal
    investigator)
  • Patient Information Sheet/Consent Form
  • Investigators Brochure
  • Subject recruitement procedures (e. g.
    advertisements)

13
BE Study Assessment Practical Issues Ethical
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 Issues Study
Protocol
15
BE Study Assessment Practical Issues Study
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 Issues Study
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 Issues Study
Protocol/Report
  • General Information/Title Page contd.
  • Investigator Details
  • Principal Investigator, Medical Doctor
  • Other Laboratory/Institution Details
  • ? Responsibilities!

18
BE Study Assessment Practical Issues Study
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 Issues Objectives
  • 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
  • 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)

23
BE Study Assessment Practical Issues
  • Drug Products
  • 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
  • Drug Products
  • 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 Issues 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 and
    informed consent
  • volunteers insurance
  • reimbursement

26
BE Study Assessment Practical Issues Study
Subjects
  • Selection of subjects
  • males or females or both gender?
  • the sponsor may wish to include both(WHO)

27
BE Study Assessment Practical Issues 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 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 Issues 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, gt
    18y)
  • randomisation
  • objective minimising interindividual
    variability in order to detect product
    differences!

29
BE Study Assessment Practical Issues Study
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 Issues Study
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 Issues Study
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 calculation provided in the study
    protocol. A minimum of 12 subjects is required.
  • WHO Technical Report Series, No. 937, Annex 7

32
BE Study Assessment Practical Issues Study
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 Issues Study
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 Issues
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)

35
BE Study Assessment Practical Issues
Standardisation
  • 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 Issues
Standardisation
  • 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 Issues
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

38
BE Study Assessment Practical Issues Study
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 Issues 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!

40
BE Study Assessment Practical Issues Study
Samples
  • Number of samples
  • sufficient to describe at least 80 of total
    AUC
  • usually 12 18 samples (minimum)

41
BE Study Assessment Practical Issues Study
Samples
42
BE Study Assessment Practical Issues
43
BE Study Assessment Practical Issues
Verapamil BE study Govi-Verlag 1989
44
BE Study Assessment Practical Issues
Exceptional 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 Issues
Exceptional Cases!
Panchagnula et al., Pharmacol Res 48 (2003) 383
46
BE Study Assessment Practical Issues
Exceptional Cases!
Panchagnula et al., Pharmacol Res 48 (2003) 383
47
BE Study Assessment Practical Issues
Exceptional Cases!
  • The comparative Spearmans 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 Issues Sampling
  • Blood withdrawal equipment (consider
    bioanalytical method)
  • Preparation of plasma or serum
  • volume
  • cooling
  • anticoagulant
  • centrifugation
  • aliquotation
  • labeling
  • freezing
  • transport

49
BE Study Assessment Practical Issues
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

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

51
BE Study Assessment Practical Issues
Calculations
  • The protocol should state (-among others-)
  • calculation procedure/methods
  • characteristics (e.g. AUC, Cmax)
  • possible consideration of differences of drug
    content
  • acceptance ranges widening acceptable?!

52
BE Study Assessment Practical Issues
Calculations
  • single dose studies
  • reg. characteristics
  • AUC extent of bioavailability (calculated by
    means of trapezoidal rule)
  • AUCt for single dose studies (t last
    quantifiable concentration)
  • AUCinf AUCt extrapolated to infinity (total
    exposure)
  • exposure

53
BE Study Assessment Practical Issues
Calculations
  • single dose studies
  • rate of bioavailability
  • Cmax observed maximum concentration (peak
    exposure)
  • tmax time at which maximum concentration occurs

54
BE Study Assessment Practical Issues
Calculations
  • multiple dose studies (exceptional cases)
  • direct switching vs. wash-out
  • primary characteristics (e.g. AUCtau, Cmax,
    Cmin)
  • consideration of fluctuation (e.g. Ptf)
  • compare Cmin to ensure steady-state

55
BE Study Assessment Practical Issues 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)
  • serious but not study drug related ?

56
BE Study Assessment Practical Issues
  • THANK YOU FOR YOUR ATTENTION
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