Transcript BE study assessment

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
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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Workshop: Training of BE Assessors, Kiev, October 2009
Some Background Information
1. drugs are usually administered as dosage forms
2. the dosage form can affect drug bioavailability
3. differences in the pharmaceutical formulation can lead to different
bioavailabilities
4. effects of formulation differences apply particularly to oral dosage
forms and may be manifest at all stages of the absorption process
5. in vitro tests provide valuable information but are not necessarily a
reliable guide to the bioavailability or therapeutic performance of the
product
6. 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/toxicological 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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
Ethical Considerations
IEC / IRB: ICH Definition
 An independent body of medical, scientific and nonscientific 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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Workshop: Training of BE Assessors, Kiev, October 2009
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 nonscientific 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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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
 Investigator´s Brochure
 Subject recruitement procedures (e. g. advertisements)
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Workshop: Training of BE Assessors, Kiev, October 2009
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
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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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, > 18y)
♦ randomisation
objective: minimising interindividual variability in order to
detect product differences!
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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
Study Samples
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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
Verapamil; BE
study; GoviVerlag 1989
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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
Exceptional Cases!
„The comparative Spearman‘s 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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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
Sampling
 Blood withdrawal equipment (consider bioanalytical method)
 Preparation of plasma or serum








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volume
cooling
anticoagulant
centrifugation
aliquotation
labeling
freezing
transport…
Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
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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Workshop: Training of BE Assessors, Kiev, October 2009
BE Study Assessment – Practical Issues
THANK YOU FOR YOUR
ATTENTION
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Workshop: Training of BE Assessors, Kiev, October 2009