3 2 BEstudy Basics

Assessment of Interchangeable Multisource Medicines
Dr. Henrike Potthast
BE Study Assessment Practical Issues
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 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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Assessment of Interchangeable Multisource Medicines, Kenya, August 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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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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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 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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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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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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Required documents
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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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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BE Study Assessment Practical Issues Study Protocol
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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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General Information/Title Page Title Protocol Number
Version Number/Date
Sponsor Details
Name, Address, Telephone Monitor/Medical Personnel
Responsibilities!
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General Information/Title Page contd.
Investigator Details
Principal Investigator, Medical Doctor
Other Laboratory/Institution Details
Responsibilities!
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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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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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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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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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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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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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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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males or females or both gender? the sponsor may wish to include both(WHO)
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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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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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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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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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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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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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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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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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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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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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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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Number of samples
sufficient to describe at least 80 % of total AUC usually ~12 18 samples (minimum)
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Study Samples
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Verapamil; BE study; GoviVerlag 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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Panchagnula et al., Pharmacol Res 48 (2003) 383
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Panchagnula et al., Pharmacol Res 48 (2003) 383
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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

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volume cooling anticoagulant centrifugation aliquotation labeling freezing transport
BE Study Assessment Practical Issues 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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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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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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single dose studies
reg. characteristics
AUC extent of bioavailability (calculated by means of

trapezoidal rule)
concentration)
AUCt for single dose studies (t = last quantifiable AUCinf AUCt extrapolated to infinity (total exposure) exposure
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single dose studies
rate of bioavailability
Cmax observed maximum concentration (peak

exposure)
tmax time at which maximum concentration occurs
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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 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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THANK YOU FOR YOUR ATTENTION
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Assessment of Interchangeable Multisource Medicines

Dr. Henrike Potthast

BE Study Assessment Practical Issues

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Some Background Information

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Bioequivalence equivalent bioavailability within pre-set acceptance ranges

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Two medicinal products are bioequivalent if they are

possible surrogate for full clinical/toxicological documentation

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

.if the fraction of the dose absorbed is the same, the

[Faassen et al. Clin Pharmacokinet 43 (2004)1117]

what does the product do to the drug substance?

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues

comparison of product characteristics in order to ensure therapeutic equivalence

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Ethical Considerations

BE Study Assessment Practical Issues Ethical Considerations

Assessment of Interchangeable Multisource Medicines, Kenya, August 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

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Ethical Considerations

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Ethical Considerations

Minimum information required by ICH-GCP:

BE Study Assessment Practical Issues Study Protocol

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Study Protocol/Report

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Study Protocol/Report

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Study Protocol/Report

Other Laboratory/Institution Details

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Study Protocol/Report

Bioanalytical phase (timely data transfer ensured?)

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Objectives

pharmacokinetics (t1/2, peak concentration, time of peak concentration,

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues

Drug substance / Drug products

important side effects (acceptable for healthy volunteers, concomitant

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues

Preparation of investigative products per volunteer acc. to GMP

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Study Subjects

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

BE Study Assessment Practical Issues Study Subjects

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009