Assessment of Interchangeable Multisource Medicines BE Study Assessment – Practical Issues
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Transcript of Assessment of Interchangeable Multisource Medicines BE Study Assessment – Practical Issues
Assessment of Interchangeable
Multisource Medicines
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues
Dr. Henrike Potthast
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |
Guidance DocumentsGuidance DocumentsGuidance DocumentsGuidance 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 20093 |
Some Background InformationSome Background InformationSome Background InformationSome 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))
Assessment of Interchangeable Multisource Medicines, Kenya, August 20094 |
DefinitionsDefinitionsDefinitionsDefinitions
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
Assessment of Interchangeable Multisource Medicines, Kenya, August 20095 |
DefinitionsDefinitionsDefinitionsDefinitions
♦ „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
Assessment of Interchangeable Multisource Medicines, Kenya, August 20096 |
DefinitionsDefinitionsDefinitionsDefinitions
♦ „…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]
Assessment of Interchangeable Multisource Medicines, Kenya, August 20097 |
DefinitionsDefinitionsDefinitionsDefinitions
♦ „….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 IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 20099 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical Considerations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200910 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical Considerations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200911 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical considerationsEthical considerations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical considerationsEthical 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200912 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical Considerations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical 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)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200913 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical Considerations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Ethical ConsiderationsEthical 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200914 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study ProtocolStudy Protocol
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study ProtocolStudy Protocol
Assessment of Interchangeable Multisource Medicines, Kenya, August 200915 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy Protocol/Report
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200916 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy Protocol/Report
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy 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 IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy Protocol/Report
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy Protocol/Report
General Information/Title Page contd.
♦ Investigator Details♦ Principal Investigator, Medical Doctor
♦ Other Laboratory/Institution Details
Responsibilities!
Assessment of Interchangeable Multisource Medicines, Kenya, August 200918 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy Protocol/Report
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study Protocol/ReportStudy 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200919 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues ObjectivesObjectives
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues ObjectivesObjectives
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?)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200920 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues BE Study Assessment – Practical IssuesBE 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?)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200921 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues BE Study Assessment – Practical IssuesBE 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?
Assessment of Interchangeable Multisource Medicines, Kenya, August 200922 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues BE Study Assessment – Practical IssuesBE 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)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200923 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE 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)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200924 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues BE Study Assessment – Practical IssuesBE 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 %
Assessment of Interchangeable Multisource Medicines, Kenya, August 200925 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200926 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
Selection of subjects
males or females or both gender? “…the sponsor may wish to include
both…”(WHO)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200927 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200928 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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!
Assessment of Interchangeable Multisource Medicines, Kenya, August 200929 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200930 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200931 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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]
Assessment of Interchangeable Multisource Medicines, Kenya, August 200932 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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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BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy Subjects
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SubjectsStudy 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!!”
Assessment of Interchangeable Multisource Medicines, Kenya, August 200934 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
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’)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200935 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200936 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200937 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues StandardisationStandardisation
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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200938 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy Samples
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy 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 particulardrug substance is inevitable!
objective: characterisation of ‚drug input‘!(see e.g. sect. 3.1 of the EU guidance 1401/98)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200939 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy Samples
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy Samples
Sampling times
appr. 3 – 4 to describe drug “input” appr. 3 sampling times around peak concentration appr. 3 – 4 to describe elimination
Minimum!
Assessment of Interchangeable Multisource Medicines, Kenya, August 200940 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy Samples
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy Samples
Number of samples
sufficient to “describe” at least 80 % of total AUC
usually ~12– 18 samples (minimum)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200941 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Study SamplesStudy Samples
Assessment of Interchangeable Multisource Medicines, Kenya, August 200942 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues
Assessment of Interchangeable Multisource Medicines, Kenya, August 200943 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues
Verapamil; BE study; Govi-Verlag 1989
Assessment of Interchangeable Multisource Medicines, Kenya, August 200944 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional Cases!!
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional 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]
Assessment of Interchangeable Multisource Medicines, Kenya, August 200945 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional Cases!!
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional Cases!!
Panchagnula et al., Pharmacol Res 48 (2003) 383
Assessment of Interchangeable Multisource Medicines, Kenya, August 200946 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional Cases!!
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional Cases!!
Panchagnula et al., Pharmacol Res 48 (2003) 383
Assessment of Interchangeable Multisource Medicines, Kenya, August 200947 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional Cases!!
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Exceptional CasesExceptional 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]
Assessment of Interchangeable Multisource Medicines, Kenya, August 200948 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues SamplingSampling
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues SamplingSampling
Blood withdrawal equipment (consider bioanalytical method)
Preparation of plasma or serum volume cooling anticoagulant centrifugation aliquotation labeling freezing transport…
Assessment of Interchangeable Multisource Medicines, Kenya, August 200949 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Bioanalytical MethodBioanalytical Method
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Bioanalytical MethodBioanalytical 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200950 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
The protocol should state (-among others-)
the transfer of bioanalytical results for biostatistical calculations
the handling of missing data
the handling of digits
Assessment of Interchangeable Multisource Medicines, Kenya, August 200951 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
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?!
Assessment of Interchangeable Multisource Medicines, Kenya, August 200952 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
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‘
Assessment of Interchangeable Multisource Medicines, Kenya, August 200953 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues CalculationsCalculations
single dose studies
‚rate‘ of bioavailability
Cmax – observed maximum concentration (peak exposure)
tmax – time at which maximum concentration occurs
Assessment of Interchangeable Multisource Medicines, Kenya, August 200954 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Calculations Calculations
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Calculations 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200955 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Adverse EventsAdverse Events
BE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues Adverse EventsAdverse 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
Assessment of Interchangeable Multisource Medicines, Kenya, August 200956 |
BE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical IssuesBE Study Assessment – Practical Issues
THANK YOU FOR YOUR ATTENTION