planning a BE study

1
Training Workshop Training of BE
Assessors Kiev, October 2009 BE Study Assessment
Practical Issues Dr. Henrike Potthast
Training workshop Training of BE Assessors,
Kiev, October 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

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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))

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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

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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

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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

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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?

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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

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BE Study Assessment Practical Issues
What do we need to know?
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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

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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

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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

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BE Study Assessment Practical Issues Ethical
Considerations

• Documents that should be available for the IRB
• Protocol (signed at least by the principal
  investigator)
• Patient Information Sheet/Consent Form
• Investigators Brochure
• Subject recruitement procedures (e. g.
  advertisements)

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BE Study Assessment Practical Issues Ethical
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

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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

Protocol
Report
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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!

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BE Study Assessment Practical Issues Study
Protocol/Report

• General Information/Title Page contd.
• Investigator Details
• Principal Investigator, Medical Doctor
• Other Laboratory/Institution Details
• ? Responsibilities!

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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

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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?)

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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?)

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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?

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BE Study Assessment Practical Issues

• Drug Products
• 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)

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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)

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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 - (dose correction?!)

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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

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BE Study Assessment Practical Issues Study
Subjects

• Selection of subjects
• males or females or both gender?
• the sponsor may wish to include both(WHO)

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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)

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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!

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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

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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

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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

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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
• comprehensive reporting in the study report

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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!!

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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)

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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

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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

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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

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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)

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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!

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BE Study Assessment Practical Issues Study
Samples

• Number of samples
• sufficient to describe at least 80 of total
  AUC
• usually 12 18 samples (minimum)

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BE Study Assessment Practical Issues Study
Samples
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BE Study Assessment Practical Issues
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BE Study Assessment Practical Issues
Verapamil BE study Govi-Verlag 1989
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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

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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

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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

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BE Study Assessment Practical Issues
Bioanalytical Method

• It should be reported what is/has been
• 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

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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

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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?!

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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

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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

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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

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BE Study Assessment Practical Issues Adverse
Events

• Definitions, handling/information/report
• 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 ?

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BE Study Assessment Practical Issues

• THANK YOU FOR YOUR ATTENTION