Transcript Planning a BE Study Training Program on Pharmaceutical Quality, Good Manufacturing

Planning a BE Study
Training Program on Pharmaceutical
Quality, Good Manufacturing
Practice and Bioequivalence
Jiaxing, Zhejiang, China
5 – 9 November 2007
Dr. Henrike Potthast ([email protected])
temporary advisor to WHO
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pt consultant to WHO | November 2007
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
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pt consultant to WHO | November 2007
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
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
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
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Definitions
♦
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]
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pt consultant to WHO | November 2007
Planning a BE Study
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 Working Document Multisource (Generic) Pharmaceutical Products:
Guidelines on Registration Requirements to Establish Interchangeability November
2005]
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
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
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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)
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Planning a BE Study
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
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pt consultant to WHO | November 2007
Planning a BE Study
Study Protocol
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pt consultant to WHO | November 2007
Planning a BE Study
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
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pt consultant to WHO | November 2007
Planning a BE Study
Study Protocol
General Information/Title Page
♦ Title
♦ Protocol Number
♦ Version Number/Date
♦ Sponsor Details
♦ Name, Address, Telephone
♦ Monitor/Medical Personnel
 Responsibilities!
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pt consultant to WHO | November 2007
Planning a BE Study
Study Protocol
General Information/Title Page contd.
♦ Investigator Details
♦ Principal Investigator, Medical Doctor
♦ Other Laboratory/Institution Details
 Responsibilities!
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Planning a BE Study
Study 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
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pt consultant to WHO | November 2007
Planning a BE Study
Protocol 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?)
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pt consultant to WHO | November 2007
Planning a BE Study
Protocol 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?)
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pt consultant to WHO | November 2007
Planning a BE Study
Protocol 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?
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pt consultant to WHO | November 2007
Planning a BE Study
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)
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pt consultant to WHO | November 2007
Planning a BE Study
Protocol Development
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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pt consultant to WHO | November 2007
Planning a BE Study
Protocol Development
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 %
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Study Subjects
 Selection of subjects
males or females or both gender?
“…the sponsor may wish to include
both…”(WHO)
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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 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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pt consultant to WHO | November 2007
Planning a BE Study
Study 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 …)
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pt consultant to WHO | November 2007
Planning a BE Study
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 – working document on multisource (generic) pharmaceutical
products (QAS/04.093)
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pt consultant to WHO | November 2007
Planning a BE Study
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
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Study Design
 Randomization to a Crossover-design
“latin square” / balanced / randomized
Volunteer
Period 1
Period 2
1
A
B
2
B
A
…
…
…
 Intra-individual comparison!
 Parallel group design
 Replicate design
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pt consultant to WHO | November 2007
Planning a BE Study
Study Design
others e.g.,
 Parallel group design
 Replicate design
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Study Samples
 Number of samples
 sufficient to “describe” at least 80 % of total AUC
 usually ~12– 18 samples (minimum)
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pt consultant to WHO | November 2007
Planning a BE Study
Study Samples
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pt consultant to WHO | November 2007
Planning a BE Study
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pt consultant to WHO | November 2007
Planning a BE Study
Verapamil; BE
study; GoviVerlag 1989
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Exceptional Cases!
Panchagnula et al.,
Pharmacol Res 48
(2003) 383
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pt consultant to WHO | November 2007
Planning a BE Study
Exceptional Cases!
Panchagnula et al.,
Pharmacol Res 48
(2003) 383
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Study Samples
 Wash-out-phase
 must be long enough to avoid residual concentrations
 closely related to the limit of quantitation
 metabolites may be considered
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pt consultant to WHO | November 2007
Planning a BE Study
Sampling
 Blood withdrawal equipment (consider bioanalytical method)
 Preparation of plasma or serum








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volume
cooling
anticoagulant
centrifugation
aliquotation
labeling
freezing
transport…
pt consultant to WHO | November 2007
Planning a BE Study
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
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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
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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pt consultant to WHO | November 2007
Planning a BE Study
Calculations
 single dose studies
 ‚rate‘ of bioavailability
 Cmax – observed maximum concentration (peak
exposure)
 tmax – time at which maximum concentration occurs
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pt consultant to WHO | November 2007
Planning a BE Study
Calculations
 multiple dose studies
 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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pt consultant to WHO | November 2007
Planning a BE Study - 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 
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pt consultant to WHO | November 2007
Planning a BE Study
THANK YOU FOR YOUR
ATTENTION
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pt consultant to WHO | November 2007