WHO Workshop on Assessment of Bioequivalence Data
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WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, August 2010 BE Study Assessment – Practical Issues Dr. Henrike Potthast ([email protected]). WHO workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August-3. September 2010. Guidance Documents.

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WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, August 2010 BE Study Assessment – Practical Issues

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Who workshop on assessment of bioequivalence data addis ababa august 2010 be study assessment practical issues dr h

WHO Workshop on Assessment of Bioequivalence Data

Addis Ababa, August 2010

BE Study Assessment – Practical Issues

Dr. Henrike Potthast ([email protected])

WHO workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August-3. September 2010


Guidance documents

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 Rev.1 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


Some background information

Some Background Information

  • drugs are usually administered as dosage forms

  • the dosage form can affect drug bioavailability

  • differences in the pharmaceutical formulation can lead to different bioavailabilities

  • effects of formulation differences apply particularly to oral dosage forms and may be manifest at all stages of the absorption process

  • in vitro tests provide valuable information but are not necessarily a reliable guide to the bioavailability or therapeutic performance of the product

  • 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))


Definitions

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


Definitions1

Definitions

♦„Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy .“

[section 1.1 of the revised EU guidance on BE]

 possible surrogate for full clinical/toxicological documentation


Definitions2

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]


Definitions3

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?


Be study assessment practical issues

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 ensure therapeutic equivalence


Be study assessment practical issues1

BE Study Assessment – Practical Issues

What do we need to know?

How to ensure bioequivalence?


Be study assessment practical issues ethical considerations

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 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” evaluation


Be study assessment practical issues ethical considerations1

BE Study Assessment – Practical IssuesEthical Considerations

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 sponsor should review on a trial-related matter


Be study assessment practical issues ethical considerations2

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


Be study assessment practical issues ethical considerations3

BE Study Assessment – Practical IssuesEthical Considerations

Documents that should be available for the IRB

  • Protocol (signed at least by the principal investigator)

  • Patient Information Sheet/Consent Form

  • Investigator´s Brochure

  • Subject recruitement procedures (e. g. advertisements)


Be study assessment practical issues ethical considerations4

BE Study Assessment – Practical IssuesEthical Considerations

Approval notification to be available in the study report

  • Timely written approval

    • Identification of study (title, protocol number, version, investigator, site)

    • Specifification of 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


Be study assessment practical issues study protocol report

BE Study Assessment – Practical IssuesStudy 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

Protocol

Report


Be study assessment practical issues study protocol report1

BE Study Assessment – Practical IssuesStudy Protocol/Report

General Information/Title Page

  • Title

  • Protocol Number

  • Version Number/Date

  • Sponsor Details

    • Name, Address, Telephone

    • Monitor/Medical Personnel

       Responsibilities!


Be study assessment practical issues study protocol report2

BE Study Assessment – Practical IssuesStudy Protocol/Report

General Information/Title Page contd.

  • Investigator Details

    • Principal Investigator, Medical Doctor

  • Other Laboratory/Institution Details

     Responsibilities!


Be study assessment practical issues study protocol report3

BE Study Assessment – Practical IssuesStudy 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


Be study assessment practical issues objectives

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


Be study assessment practical issues2

BE Study Assessment – Practical Issues

Drug substance / Drug products

basic knowledge about particularities e.g.

  • important side effects(acceptable for healthy volunteers or is there a need for a study in patients?, concomitant medication necessary, acceptable regarding evaluation (e.g. vomiting); acceptable for women with childbearing potential?)


Be study assessment practical issues3

BE 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 acceptable/necessary/possible?


Be study assessment practical issues4

BE Study Assessment – Practical Issues

DrugProducts

  • Availability

  • Certification

    • Content/Potency

    • (comparative) in-vitro dissolution

  • Preparation of investigative products per volunteer acc. to GMP

  • Protocol amendment for product details frequently necessary -

    (e. g. labeling)


Be study assessment practical issues5

BE Study Assessment – Practical Issues

DrugProducts

  • batch size

    • pilot batch?

    • commercial batch?

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

    - this is of particular importance -


Be study assessment practical issues6

BE Study Assessment – Practical Issues

DrugProducts (WHOTechn. Rep. Series No. 937 May 2006 Annex 7, sect. 6.5.1)

  • “…Batch-control results of the multisource product, and the lot numbers and expiry dates of both multisource and comparator products should be stated….

  • It is recommended that potency and in vitro dissolution characteristics of the multisource and the comparator pharmaceutical products be ascertained prior to performance of an equivalence study….”


Be study assessment practical issues7

BE Study Assessment – Practical Issues

DrugProducts

  • assay

    • close to label claim

    • difference regarding the content of the investigative products (T and R) should preferably be not more

      than 5 % - (“dose correction”?!)


Be study assessment practical issues8

BE Study Assessment – Practical Issues

DrugProducts

  • Dose to be investigated (WHOTechn. Rep. Series No. 937 May 2006 Annex 7, sect. 6.6.1)

    “In bioequivalence studies the molar equivalent dose of multisource and comparator product must be used.”


Be study assessment practical issues9

BE Study Assessment – Practical Issues

DrugProducts

  • Dose to be investigated ctd.(WHOTechn. Rep. Series No. 937 May 2006 Annex 7, sect. 6.6.1) – product series

  • “Generally the marketed strength with the greatest sensitivity to bioequivalence assessment should be administered as a single unit. This will usually be the highest marketed strength. A higher dose (i.e. more than one dosage unit) may be employed when analytical difficulties exist. In this case the total single dose should not exceed the maximal daily dose of the dosage regimen. Alternatively, the application of area under the curve (AUC) truncated to 3 × median tmax of the comparator formulation would avoid problems of lack of assay sensitivity in many cases. In certain cases a study performed with a lower strength can be considered acceptable if this lower strength is chosen for reasons of safety.”


Be study assessment practical issues10

BE Study Assessment – Practical Issues

DrugProducts

  • Dose to be investigated ctd.– product series

  • Cave: – if AUC increases less than proportional with dose then the lower dose may be most sensitive -


Be study assessment practical issues study subjects

BE Study Assessment – Practical IssuesStudy 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


Be study assessment practical issues study subjects1

BE Study Assessment – Practical IssuesStudy Subjects

  • Selection of subjects

    • males or females or both gender?

    • “…the sponsor may wish to include both…”(WHO)


Be study assessment practical issues study subjects2

BE Study Assessment – Practical IssuesStudy 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)


Be study assessment practical issues study subjects3

BE Study Assessment – Practical IssuesStudy Subjects

  • Selection of subjects ctd. (WHOTechn. Rep. Series No. 937, sect. 6.3.5)

  • “Phenotyping for metabolizing activity can be of importance for studies with high-clearance drugs that are metabolized by enzymes that are subject to genetic polymorphism, e.g. propranolol. In such cases, slow metabolizers will have a higher bioavailability of the parent drug, while the bioavailability of possible active metabolites will be lower. Phenotyping of subjects can be considered for studies of drugs that show phenotype-linked metabolism and for which a parallel group design is to be used… Phenotyping could also be important for safety reasons, determination of samplingtimes and wash-out periods in cross-over design studies.”


Be study assessment practical issues study subjects4

BE Study Assessment – Practical IssuesStudy Subjects

  • Selection of subjects

    • description of volunteers;smoker, vegetarian, phenotyping….

      EU: healthy, BMI; FDA: both sexes, > 18y; WHO: 18-55y)

    • verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure…)

    • number of volunteers depending on variability (at least 12)

    • randomisation

      objective: minimising interindividual variability in order to detect possible product differences!


Be study assessment practical issues study subjects5

BE Study Assessment – Practical IssuesStudy 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


Be study assessment practical issues study subjects6

BE Study Assessment – Practical IssuesStudy 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


Be study assessment practical issues study subjects7

BE Study Assessment – Practical IssuesStudy Subjects

  • Number of subjects ctd

    • “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 calculationprovided in the study protocol. A minimum of 12 subjects is required.”

      [WHO Technical Report Series, No. 937, Annex 7]


Be study assessment practical issues study subjects8

BE Study Assessment – Practical IssuesStudy 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

    • comprehensive reporting in the study report


Be study assessment practical issues study subjects9

BE Study Assessment – Practical IssuesStudy 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!!”


Be study assessment practical issues standardisation

BE Study Assessment – Practical IssuesStandardisation

  • 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’)


Be study assessment practical issues standardisation1

BE Study Assessment – Practical IssuesStandardisation

  • 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


Be study assessment practical issues standardisation2

BE Study Assessment – Practical IssuesStandardisation

  • 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


Be study assessment practical issues standardisation3

BE Study Assessment – Practical IssuesStandardisation

  • 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 and formulation robustness


Be study assessment practical issues standardisation4

BE Study Assessment – Practical IssuesStandardisation

  • Fed state ctd: (WHO Technical Report Series, No. 937, Annex 7, sect. 6.4)

    „Some medicines are normally given with food to reduce gastrointestinal side-effects; in certain cases coadministration with food increases bioavailability of orally administered preparations. If the labelling states that the pharmaceutical product should be taken with food then a fed study should be used to assess bioequivalence. Fed state studies are also required in bioequivalence studies of modified release formulations. In these cases the objective is to select a meal that will challenge the robustness of the new multisource formulation to prandial effects on bioavailability (see 6.2.4). The test meal selected should take account of local custom and diet and should be consumed within 20 minutes. The product should be administered according to the protocol and within 30 minutes after the meal has been eaten.“


Be study assessment practical issues study samples

BE Study Assessment – Practical IssuesStudy 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‘!


Be study assessment practical issues study samples1

BE Study Assessment – Practical IssuesStudy Samples

  • Sampling times

    • appr. 3 – 4 to describe drug “input”

    • appr. 3 sampling times around peak concentration

    • appr. 3 – 4 to describe elimination

       Minimum!


Be study assessment practical issues study samples2

BE Study Assessment – Practical IssuesStudy Samples

  • Number of samples

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

    • usually ~12– 18 samples (minimum)


Be study assessment practical issues study samples3

BE Study Assessment – Practical IssuesStudy Samples

  • WHO Technical Report Series 937 Annex 7 sect. 6.6.2

    “Blood samples should be taken at a frequency sufficient for assessing Cmax, AUC and other parameters. Sampling points should include a pre-dose sample, at least 1–2 points before Cmax, 2 points around Cmax and 3–4 points during the elimination phase. Consequently at least seven sampling points will be necessary for estimation of the required pharmacokinetic parameters. For most medicines the number of samples necessary will be higher to compensate for between-subject differences in absorption and elimination rate and thus enable accurate determination of the maximum concentration of the API in the blood (Cmax) and terminal elimination rate constant in all subjects..”


Be study assessment practical issues study samples4

BE Study Assessment – Practical IssuesStudy Samples

  • WHO Technical Report Series 937 Annex 7 sect. 6.6.2

    “Generally, sampling should continue for long enough to ensure that 80% of the AUC (0→ infinity) can be accrued, but it is not necessary to sample for more than 72 hours. The exact duration of sample collection depends on the nature of the API and the input function from the administered dosage form (see also 6.11.4).”


Be study assessment practical issues study samples5

BE Study Assessment – Practical IssuesStudy Samples

  • WHO Technical Report Series 937 Annex 7 sect. 6.2.2

    “For both cross-over and parallel-design studies, sample collection time should be adequate to ensure completion of gastrointestinal transit (approximately 2–3 days) of the pharmaceutical product and absorption of the API. Blood sampling up to 72 hours following administration should be carried out, unless shorter periods can be justified.”


Who workshop on assessment of bioequivalence data addis ababa august 2010 be study assessment practical issues dr h

BE Study Assessment – Practical IssuesStudy Samples


Be study assessment practical issues11

BE Study Assessment – Practical Issues


Be study assessment practical issues12

BE Study Assessment – Practical Issues

Verapamil; BE study; Govi-Verlag 1989


Be study assessment practical issues exceptional cases

BE Study Assessment – Practical IssuesExceptional 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]


Be study assessment practical issues exceptional cases1

BE Study Assessment – Practical IssuesExceptional 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]


Be study assessment practical issues sample fluids and collection

BE Study Assessment – Practical IssuesSample Fluids and Collection!

„Blood samples should be processed and stored under conditions that have been shown not to cause degradation of the analytes. This can be proven by analysing duplicate quality control samples during the analytical period. Quality control samples must be prepared in the fluid of interest (e.g. plasma), including concentrations at least at the low, middle and high segments of the calibration range. The quality control samples must be stored with the study samples and analysed with each set of study samples for each analytical run.

The sample collection methodology must be specified in the study protocol.“

[WHO Technical Report Series 937 Annex 7 sect. 6.6.3]


Be study assessment practical issues sampling

BE Study Assessment – Practical IssuesSampling

  • Blood withdrawal equipment (consider bioanalytical method)

  • Preparation of plasma or serum

    • volume

    • cooling

    • anticoagulant

    • centrifugation

    • aliquotation

    • labeling

    • freezing

    • transport…


Be study assessment practical issues bioanalytical method

BE Study Assessment – Practical IssuesBioanalytical Method

  • It should be reported what is/has been …

    • the bioanalytical method/detection

    • the limit of quantitation (1/20 of the expected peak concentration should be measurable)

    • the validation concept

    • whether metabolites are to be considered

    • enantioselective method necessary?


Be study assessment practical issues bioanalytical method1

BE Study Assessment – Practical IssuesBioanalytical Method!

„Generally, evaluation of pharmacokinetic bioequivalence will be based upon the measured concentrations of the parent drug released from the dosage form rather than the metabolite. The concentration–time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution and elimination. It is important to state a prioriin the study protocol which chemical entities (pro-drug, drug (API) or metabolite) will be analysed in the samples.„

[WHO Technical Report Series 937 Annex 7 sect. 6.6.5]


Be study assessment practical issues bioanalytical method2

BE Study Assessment – Practical IssuesBioanalytical Method!

„A non-stereoselective assay is currently acceptable for most pharmacokinetic bioequivalence studies. When the enantiomers have very differentpharmacological or metabolic profiles, assays that distinguish between the enantiomers of a chiral API may be appropriate. Stereoselective assay is also preferred when systemic availability of different enantiomers is demonstrated to be non-linear.„

[WHO Technical Report Series 937 Annex 7 sect. 6.6.6]


Be study assessment practical issues bioanalytical method3

BE Study Assessment – Practical IssuesBioanalytical Method!

„All analytical test methods used to determine the active compound and/or its biotransformation product in the biological fluid must be well characterized, fully validated and documented. The objective of the validation is to demonstrate that a particular method used for quantitative measurement of analytes in a given biological matrix, such as blood, plasma, serum or urine, is reliable and reproducible for the intended use…“

[WHO Technical Report Series 937 Annex 7 sect. 6.7]


Be study assessment practical issues calculations

BE Study Assessment – Practical IssuesCalculations

  • The protocol should state(-among others-)

    • the transfer of bioanalytical results for biostatistical calculations

    • the handling of missing data

    • the handling of digits


Be study assessment practical issues calculations1

BE Study Assessment – Practical IssuesCalculations

  • 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 or even tighter accepance limits needed?!


Be study assessment practical issues calculations2

BE Study Assessment – Practical IssuesCalculations

  • 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‘


Be study assessment practical issues calculations3

BE Study Assessment – Practical IssuesCalculations

  • single dose studies

    • ‚rate‘ of bioavailability

    • Cmax – observed maximum concentration(peak exposure)

    • tmax – time at which maximum concentration occurs


Be study assessment practical issues calculations4

BE Study Assessment – Practical Issues Calculations

  • multiple dose studies (exceptional cases)

    „Single dose studies are preferred to multiple-dose studies as single-dose studies are considered to provide more sensitive measurements of the release of API from the pharmaceutical product into the systemic circulation. Multiple-dose studies may need to be considered (in addition to a single dose study) for extended-release dosage forms with a tendency to accumulate.“ (WHO TRS937 Annex 7; 6.2.4)


Be study assessment practical issues calculations5

BE Study Assessment – Practical Issues 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 issues safety adverse events

BE Study Assessment – Practical Issues Safety/Adverse Events

  • Definitions, handling/information/report

    • 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 


Be study assessment practical issues proportionality biowaiver

BE Study Assessment – Practical Issues Proportionality Biowaiver

  • Biowaiver based on dose-proportionality of formulations

    „A prerequisite for qualification for a biowaiver based on dose-proportionality of formulations is that the multisource product at one strength has been shown in in vivo studies to be bioequivalent to the corresponding strength of the comparator product. The second requirement is that the further strengths of the multisource product are proportionally similar in formulation to that of the strength studied. When both of these criteria are met and the dissolution profiles of the further dosage strengths are shown to be similar to that of the strength studied on a percentage released against time basis, the biowaiver procedure can be considered for the further strengths…“

    (WHO TRS 937 Annex 7; sect. 9.3)


Be study assessment practical issues proportionality biowaiver1

BE Study Assessment – Practical Issues Proportionality Biowaiver

  • Biowaiver based on dose-proportionality of formulations ctd.

    „For the purpose of this guidance proportionally similar formulations can be defined in two ways, based on the strength of dosage forms.

    (i) All active and inactive ingredients are exactly in the same proportions in the different strengths (e.g. a tablet of 50 mg strength has all the active and inactive ingredients exactly half that of a tablet of 100 mg strength, and twice that of a tablet of 25 mg strength)….“

    (WHO TRS 937 Annex 7; sect. 9.3)


Be study assessment practical issues proportionality biowaiver2

BE Study Assessment – Practical Issues Proportionality Biowaiver

  • Biowaiver based on dose-proportionality of formulations ctd.

    (ii) For a high potency API, where the amount of the API in the dosage form is relatively low (up to 10 mg per dosage unit), the total weight of the dosage form remains nearly the same for all strengths (within ± 10% of the total weight), the same inactive ingredients are used for all strengths, and the change in strength is obtained by altering essentially only the amount of the API(s).

    (WHO TRS 937 Annex 7; sect. 9.3)


Remember

Remember

  • Bioequivalence – equivalent bioavailability within pre-set acceptance ranges

  • Pharmaceutical equivalence Bioequivalence

  • Bioequivalence Therapeutic equivalence


Be study assessment practical issues13

BE Study Assessment – Practical Issues

THANK YOU FOR YOUR ATTENTION


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