Transcript 10. Bekanntmachung gemäss § 26 des Arzneimittelgesetzes (AMG

Bundesinstitut für Arzneimittel und Medizinprodukte
World Health Organization
Training Workshop on Pharmaceutical
Quality, Good Manufacturing Practice &
Bioequivalence
Planning a BE Study
Kiev, October 3 – 7, 2005
Dr. H. Potthast ([email protected])
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Bundesinstitut für Arzneimittel und Medizinprodukte
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
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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
♦ „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]
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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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Bundesinstitut für Arzneimittel und Medizinprodukte
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
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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
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Study Protocol
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Bundesinstitut für Arzneimittel und Medizinprodukte
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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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!
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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
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Bundesinstitut für Arzneimittel und Medizinprodukte
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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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
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Ethical Considerations
Required documents

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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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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
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Study Protocol
Protocol Development
Definition of Responsibilities
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Organisation, premises, personnel & QMS
Clinical phase
Bioanalytical phase
Statistics and reporting
Archival
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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?)
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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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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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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)
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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
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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
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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
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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, followup…)
 concomitant medication
 reporting
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Study Design
 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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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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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
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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 xanthinefree liquid
 Light standardized meal not before ~4 h post-dose
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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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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)
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Study Samples
 Number of samples
 sufficient to “describe” at least 80 % of total AUC
 usually ~12 – 18 samples
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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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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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Sampling
 Blood withdrawal equipment
(consider bioanalytical
method)
 Preparation of plasma or serum
 cooling
 centrifugation
 aliquotation
 labeling
 freezing
 transport…
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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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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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Calculations
 The protocol should state (-among others-)
 calculation procedure/methods
 primary characteristics
 possible consideration of differences of drug
content
 acceptance ranges
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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)
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Study protocol
?ANY MORE QUESTIONS?
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