3 2 BEstudy Basics

8/2/2019 3 2 BEstudy Basics

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Assessment of

InterchangeableMultisource Medicines

BE Study Assessment Practical IssuesDr. Henrike Potthast

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


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

Guidance Documents

WHO Technical Report Series No. 937 May 2006:

Annex 7: Multisource (generic pharmaceutical products: Guidelines onRegistration Requirements to Establish Interchangeability

EU Note for Guidance on the Investigation of Bioavailability andBioequivalence

CPMP/EWP/QWP/1401/98 and related guidances and documents(www.emea.eu.int/pdfs/human/ewp )

FDA - Guidance for Industry: Bioavailability and Bioequivalence Studiesfor Orally Administered Drug ProductsGeneral Considerations (Oct.2000)

Canadian Guidance for Industry: Conduct and Analysis of Bioavailability

and Bioequivalence Studies Part A: Oral Dosage Formulations used forsystemic effects. (1992).and related/others


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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 differentbioavailabilities

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 necessarilyareliable guide to the bioavailability or therapeutic performance of theproduct

6. therapeutic equivalence between like formulations should not be

assumed, unless therapeutic equivalence (bioequivalence) has beendemonstrated in man; nor should therapeutic equivalence be assumedsimply 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

Bioavailabilityrate and extent at which a drugsubstance... becomes available in the general system(product characteristic!)

Bioequivalenceequivalent bioavailability within pre-setacceptance ranges

Pharmaceutical equivalence Bioequivalence

Bioequivalence Therapeutic equivalence


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Definitions

Two medicinal products are bioequivalent if they arepharmaceutically equivalent or pharmaceutical alternativesANDif their bioavailabilities after administration in the samemolar dose are similar to such degree that their effects,

with respect to both efficacy and safety, will be essentiallythe 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 subsequentabsorption 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, thehuman body should always do the same with theabsorbed compound Even in a disease state, thisargument is still a valid statement.

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

what does theproductdo to the drug substance?


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BE 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 ensuretherapeutic equivalence


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BE Study Assessment Practical IssuesEthical 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 subjectsinvolved in a trial

Among other things, reviewing, approving, and providingcontinuing review of trial protocol and amendments and ofthe methods and material to be used in obtaining anddocumenting informed consent of the trial subjects;

IndependentRisk-benefit evalution


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Composition requirementsICH 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 sponsorshould review on a trial-related matter


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BE Study Assessment Practical IssuesEthical 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

Minimuminformation required by ICH-GCP:

Date of the meeting

Documents reviewed (versions & dates)

List of members


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BE Study Assessment Practical IssuesStudy Protocol

BE S d A P i l I
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BE Study Assessment Practical IssuesStudy Protocol/Report

A document that describes the objective(s), design,

methodology, statistical consideration and organisationof a trial. It usually gives the background and rationaleof the trial

Ref.: ICH GCP Guidance

BE St d A t P ti l I


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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

BE St d Assessment Practical Iss es


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BE Study Assessment Practical IssuesObjectives

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 periodand/or wash-out period(crossover study possible?)


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important side effects(acceptable for healthy volunteers, concomitantmedication 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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DrugProducts

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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DrugProducts

batch size

pilot batch?

commercial batch?

not smaller than 100 000 units or 10 % of industrialbatch size (whichever is higher)


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DrugProducts

assay

close to label claim

difference regarding the content of the investigativeproducts (T and R) should preferably not be more

than 5 %



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BE Study Assessment Practical IssuesStudy Subjects

Selection of subjects

participation of healthyvolunteers (in vivo model)

reasonable inclusion and exclusion criteria (protocol andCRFs)

comprehensive verbal and written information and informedconsent

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; variabilityreduction/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 bloodchemistry, 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 literatureor 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 meandifference 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 MetabPharmacokinet 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 byappropriate methods (). The number of

recruited subjects should always be justified withthe sample size calculation provided in the studyprotocol. 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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yStudy Subjects

Subject withdrawals contd

subject must adhere to study requirements but

define a time frame regarding vomiting depending also onpharmacokinetics of the drug substance, e.g. volunteersmust be withdrawn in case vomiting occurs within 4 hpostdose

pre-specify!!



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yStandardisation

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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yStandardisation

Fasted statee.g.

Confinement of subjects at least 10 h prior to drugadministration

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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yStandardisation

Standardized fluid and food intake(time, composition, amount)

Prohibition of alcohol

Restriction of xanthins(coffee*, tea, coke, chocolate, chewinggum, grapefruit.)

Standardized posture

Restriction of physical activities

*cave: withdrawal may cause headache



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yStandardisation

Fed state

Define time of drug administration and food intake, (e. g. drugintake within 30 min. before, immediately before or after thestandardised 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 (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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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

Number of samples

sufficient to describe at least 80 % of total AUC

usually ~12 18 samples (minimum)

BE Study Assessment Practical Issue


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Study Samples



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Verapamil; BEstudy; Govi-Verlag 1989

BE Study Assessment Practical IssuesE i l C !


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Exceptional Cases!

Cmax is affected by the sampling points oftruncated screening protocol. As isoniazid andpyrazinamide are highly soluble and highly permeablemolecules 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]

BE Study Assessment Practical IssuesE ti l C !


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Exceptional Cases!

Panchagnula et al.,Pharmacol Res 48

(2003) 383



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Exceptional Cases!

Panchagnula et al.,Pharmacol Res 48(2003) 383



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Exceptional Cases!

The comparative Spearmans correlation analysis onthe pharmacokinetic parameters Cmax, AUCt andAUCinf 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 sufficientfor demonstration of comparative bioavailability and

bioequivalence of INH, RMP, PZA, and EMB, and thata schedule of six time points..is not adequatelyreliable for determining the bioavailability andbioequivalence of anti-tuberculosis FDCs.

[Gabriels et al., Int J Tuberc Lung Dis 11 (2007) 181]

BE Study Assessment Practical IssuesSampling


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Sampling

Blood withdrawal equipment (consider bioanalytical method)

Preparation of plasma or serum volume

cooling

anticoagulant centrifugation

aliquotation

labeling

freezing

transport

BE Study Assessment Practical IssuesBioanalytical Method


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Bioanalytical Method

The protocol should state

the bioanalytical method/detection

the limit of quantitation (1/10 of the expected peak concentrationshould be measurable)

the validation concept

whether metabolites are to be considered

BE Study Assessment Practical IssuesCalculations


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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

characteristics (e.g. AUC, Cmax)

possible consideration of differences of drug content

acceptance ranges widening acceptable?!



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Calculations

single dose studies

reg. characteristics

AUC extent of bioavailability(calculated by means oftrapezoidal rule)

AUCt for single dose studies(t = last quantifiableconcentration)

AUCinf AUCt extrapolated to infinity(total exposure)

exposure



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Calculations

single dose studies

rate of bioavailability

Cmax observed maximum concentration(peakexposure)

tmax time at which maximum concentration occurs



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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

BE Study Assessment Practical IssuesAdverse Events


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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 tested a priori forpossible analytical interferences)

serious but not study drug related



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y

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