Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 World Health Organization Training Workshop on Pharmaceutical Quality, Good Manufacturing.

Bundesinstitut für Arzneimittel und Medizinprodukte

Pt WHO-consultant 1

World Health OrganizationTraining Workshop on Pharmaceutical

Quality, Good Manufacturing Practice & Bioequivalence

Planning a BE Study

Kiev, October 3 – 7, 2005

Dr. H. Potthast ([email protected])


Pt WHO-consultant 2

Guidance DocumentsGuidance Documents

EU “Note for Guidance on the Investigation ofBioavailability 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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DefinitionsDefinitions

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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♦ „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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♦ „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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♦ ….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 ObjectivesBE 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 DesignChoice 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


Pt WHO-consultant 9

Study ProtocolStudy Protocol


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♦ „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




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!



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 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




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



Ethical Ethical CConsiderationsonsiderations

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




Required documents

Protocol (signed at least by the principal investigator) Patient Information Sheet/Consent Form Investigator´s Brochure Subject recruitement procedures (e. g.

advertisements)




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




Protocol Development

Definition of Responsibilities

Organisation, premises, personnel & QMS Clinical phase Bioanalytical phase Statistics and reporting Archival



Protocol DevelopmentProtocol 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?)



Protocol DevelopmentProtocol 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)



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!




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)




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




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




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




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, follow-up…)

concomitant medication reporting



Study DesignStudy Design

Crossover-design“latin square” / balanced / randomized

Intra-individual comparison! Parallel group design Replicate design

Volunteer Period 1 Period 2

1 A B

2 B A

… … …



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’)




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




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 xanthine-

free liquid Light standardized meal not before ~4 h post-dose




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



Study SamplesStudy 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)




Number of samples

sufficient to “describe” at least 80 % of total AUC

usually ~12 – 18 samples




Sampling times

appr. 3 – 4 to describe drug “input” appr. 3 sampling times around peak concentration appr. 3 – 4 to describe elimination

Minimum!




Wash-out-phase

must be long enough to avoid residual concentrations

closely related to the limit of quantitation

metabolites may be considered





SamplingSampling

Blood withdrawal equipment (consider bioanalytical method)

Preparation of plasma or serum cooling centrifugation aliquotation labeling freezing transport…



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



CalculationsCalculations

The protocol should state (-among others-)

the transfer of bioanalytical results for biostatistical calculations

the handling of missing data

the handling of digits



CalculationsCalculations

The protocol should state (-among others-)

calculation procedure/methods

primary characteristics

possible consideration of differences of drug content

acceptance ranges



Adverse EventsAdverse 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)



Study protocolStudy protocol

?ANY MORE QUESTIONS?

Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 World Health Organization Training Workshop on Pharmaceutical Quality, Good Manufacturing.

Documents

study protocol slide

ich gcp guidance slide

trialrelated matter

ba studies

reference medicinal

eu guidance

medicinal products

generic medicinal product