a-bioéquivalence: considérations techniques et

A-Bioéquivalence:

considérations techniques et

scientifiques

2021

Une revue technique récente en

français

A1-Bioequivalence :

Origine du concept

Principe de l’essai de bioéquivalence

?=

Approche analytiqque

Equivalence pharmaceutique: 95-105% au moins 24 moisLevothyrox: ancienne formulation: up to 110% pour 36 mois

Principe de l’essai de bioéquivalence

?=

Approche in vivo

Bioéquivalence: ≤80-125% avec un risque <5%:

Concentrations

plasmatiques

Concentrations

plasmatiques

A2: Pourquoi des preuves

pharmacocinétique (mesure des

concentrations plasmatiques) pour

démontrer la bioéquivalence plutôt

qu’un essai clinique ou la mesure

d’effets?

Essais cliniques

• Coût prohibitif annulant l’intérêt des

génériques

– Coût> plusieurs 100M€

– Générique: beaucoup moins cher mais 32M€ pour

le lévothyrox

• Impossibilité statistique de démontrer une

équivalence

– On sait démontrer une non-infériorité mais pas une

équivalence avec un intervalle 80-125% avec un

risque de 5%

Pourquoi des concentrations plasmatiques et pas des effets

L’hypothèse de base est que si les

concentrations plasmatiques sont très

proches (similaires) alors les tous effets

seront “essentiellement” les mêmes.

Is there an univocal relationship between exposure and effect ?

Basic assumption to bioequivalence

Yes/No ?

yes

yes

Effectsnot driven by plasma

concentrations

Plasma concentrations

DOSE Effectsdriven by plasma

concentrations

Yes

Plasma concentrations

yesYes

A3-Pourquoi utiliser le

concept de biodisponibilité

pour démontrer une

bioéquivalence


Similar plasma concentration profile same effect ?

Why ?

Effect = Emax Dose

ED50 + Dose

Hybrid substance and formulation properties (Potency)

Substance property (efficacy)

Effect

Emax

ED50Dose

ED50 =


Clearance EC50

Bioavailability

Substance property

Formulation property

• Similar plasma concentration profile

same effect?


Effect = Emax Dose

Clearance EC50 + Dose

F%

substance properties

Formulation properties


• Similar plasma concentration same effect?

• Comparison of 2 formulations of the same drug

Effect, pioneer = Emax Dose

Clearance EC50

F,ref

Effect,test = Emax Dose

Clearance EC50

F,test

Vs.

Comparison of test and reference formulations rely on comparison of F%ref and F%test because only F% may differ

Clearance, Emax and EC50 are substance' properties and are identical for a princeps and a generic

+ Dose + Dose

A4- Ne pas confondre essai de

bioéquivalence

et un essai de biodisponibilité

- Bioavailability trials must document

influence of different factors on the rate

and extent of drug absorption

• age

• sex

• route of administration

• disease

• •••••

Bioequivalence vs. Bioavailability (I)

Bioavailability trials :

•Variability has to be introduced deliberately

Bioequivalence trials :

•Variability must not be introduced deliberately

•Bioequivalence trial must be performed on

homomogeneous groups of subjects

Bioequivalence vs. Bioavailability (III)

- Bioavailability

No generalization from a subgroup of subjects to the

population

- Bioequivalence

If B.E. is demonstrated in a particular subgroup of

subjects, conclusion should be extended to whole

population unless there is an interaction between

formulation and a constitutional factor

Inference from a trial

Bioequivalence vs. Bioavailability (IV)

A5-Does essentially the same

plasma time curve leads to

essentially the

same effect whether toxic or

therapeutic?

PK/PD relationship to discuss

bioequivalence acceptance criteria

Exposure∆ = 20%

Eff

ect

Drug with a large margin

of safety

Dose may be selected in

the asymptotic part of the

dose-effect relationship

curve and a Δ of 20% for

exposure is generally

irrelevant in terms of effect

PK/PD relationship to discuss

bioequivalence acceptance criteria

Exposure∆ = 20%

Eff

ect

Drug with a narrow margin of safety

Dose cannot be selected in the

asymptotic part of the dose-effect

relationship curve and a Δ of 20% for

exposure may be very relevant in term of

effect depending of the slope of the

curve

Conséquence d’une variation de ± 20 % de

l’exposition sur l’amplitude des variations des

effets désirés (courbe bleue) et des effets

indésirables (courbe brune)

A6-Les différentes définitions

statistiques possibles d’ une

bioéquivalence

Average

vs.

population bioequivalence

vs.

individual bioequivalence

Different types of bioequivalence

• Average (ABE) : mean

• Population (PBE) : prescriptability

• Individual (IBE) : switchability

Interchangeability

Interchangeability

Prescribability

New patient

Switchability

Patient already under treatment and well titrated

EMA guideline

Average bioequivalence

reference

test

Same mean

AUC/ Cmax


Average B.E. refers to the location parameters

Average B.E. may not be sufficient to

guarantee that an individual patient could be

switched from a reference to a generic

formulation

(e.g., more than 50 % of subjects may be

outside the B.E. range when the average B.E.

is actually demonstrated as for the levothyrox)

Lévothyrox

Vert: sujets dont le rapport NF/VF est entre 0.9-1.11

Orange et vert : sujets dont le rapport NF/VF est entre 0.80 et -1.25

Rouge : sujet en dehors de l’intervalle d’équivalence 0.8-1.25


• Addresses only mean (center of distribution)

but not variability (shape of distribution)

• Does not address switchability (commutabilité)

• FDA : an approved generic can be a substitute for

the reference drug product; however FDA did not

indicate that the approved generic drug and the

innovative can be used interchangeability (Chow

et al: Some thoughts on drug interchangeability.)

https://www.ncbi.nlm.nih.gov/pubmed/?term=chow+sc+chenm++song+f

Prescribability

• Refer to the clinical setting in which a

practitioner prescribes a drug product to a

patient for the first time

• He has no information on his patient

• the prescriber needs to know the

comparability of the 2 or n formulations in

the population

population bioequivalence

Population bioequivalence

AUC distribution

“Test” and “reference” are bioequivalent if the entire

population distribution (mean and variability) are sufficiently

similar with regard to AUC and Cmax

Yes No

Bioéquivalence moyenne et

fenêtre thérapeutique

Switchability

• Refer to the clinical setting in which a practitioner

transfers a patient from one drug product to

another

• We have information on the response of the

patient to a particular formulation (princeps or a

generic) and clinicians have titrated the dose to

reach a particular goal

• issue for drug of critical therapeutic categories, for

elderly, debilitated patients etc.

Individual bioequivalence

patient-by-formulation interaction

YES

No

Address switchability“Test” and “reference” are bioequivalent if the individual subject means and

variabilities are sufficiently similar with regard to AUC and Cmax;

Ce concept est pratiquement abandonné car trop difficile à mettre en évidence

test

reference

Individual bioequivalence

• The clinical relevance of a subject-by-

formulation interaction has not clearly

been demonstrated

–e.g.: a pH-specific excipient effect

associated with certain diazepam

formulations result in producing

unequivalence when administered to

individuals with elevated gastric pH (like

elderly)

The types of bioequivalence:

summary

Average Population Individual

Pioneer

Test

Only guarantees on the mean

Guarantees an overall distribution (mean and variance)

Test of no interaction between patient and formulation guarantees an individual BE

Substitution entre les génériques

Generic 1

Pioneer

?

yes yes

yes

Generic 2

Generic 3

?

Other reference

medicinal product???

Différences entre génériques: AUC

0.70 0.75 0.80 0.85 0.90 0.95 1.00 1.05 1.10 1.15 1.20 1.25 1.30

AUC Point Estimate (T/R)

0

10

20

30

40

Perc

en

t (%

)

Possibilité théoriques de faire des

méta-analyses pour vérifier que les

génériques sont BE entre eux mais

les résultats seraient ingérables en

cas de différence

Chow SC, Shao J. Bioequivalence review for drug

interchangeability. J Biopharm Stat 1999;9(3):485-97.

Guideline on the investigation

of bioequivalence (2009)

• It is said: Furthermore, this guideline does not cover aspects related to generic substitution as this is subject to national legislation.

• Ce n’est pas un problème « scientifique » mais une mesure de gestion

B-The Bioequivalence

trial

B1-Types of Bioequivalence

trials

Metabolite

Drug C (t)

Drugin

urine

PD1

PD2

.....

Clinicalefficacy

Dose

PK PD Clinical

in vivo testingin vitro testing

Dissolution

abs

Types of bioequivalence trials

Types of bioequivalence trial in vivo : metabolite plasma profile (I)

• When no analytical technique

exists for drug but does exist for a

primary inactive metabolite

• The administered drug is a prodrug

which is very rapidly transformed

to an active metabolite

Pourquoi ne pas utiliser des

effets ou des essais cliniques

plutôt que des concentrations

plasmatiques pour démontrer

une BE?

Essais cliniques

• Coût prohibitif annulant l’intérêt des

génériques

– Coût> plusieurs 100M€

– Générique: beaucoup moins cher mais 32M€ pour

le lévothyrox

• Impossibilité statistique de démontrer une

équivalence

– On sait démontrer une non-infériorité mais pas une

équivalence avec un intervalle 80-125% avec un

risque de 5%

Response A

100 %

50 %

Systemic exposure

ReferenceTest

AUC

T and R are not bioequivalent

Types of Bioequivalence trialPharmacodynamic endpoints

Effe

ct

Response B

100 %

50 %

Systemic exposure

ReferenceTest

T and R are bioequivalent

AUC

Types of Bioequivalence trialPharmacodynamic endpoints

Effect

Pharmacodynamic endpoint

• An essential component of BE study

based on a PD response is documentation

of a dose-response relationship

• The BE should be conducted in the

sensitive region of dose-response curve

• A BE study conducted near the plateau of

response will be insensitive to differences

in drug

Locally acting drug products

• Issue: measurable concentrations of drug

in an accessible biological fluid may not

be produced or the clinical efficacy may

not be correlated to systemic levels

• Solution (FDA): other approaches for

assessing BE

– pharmacodynamic endpoint

– clinical endpoint

– in vitro studies

Generally, poor metrological performance

Approche retenue pour les biosimilaires

Type of Bioequivalence trial : clinical trial

Exceptions aux essais in vivo et

possibilité de les remplacer par

des tests in-vitro de dissolution

IV solutions (EMEA 2009)

• Bioequivalence studies are not required if the test product is to be administered as an aqueous intravenous solution containing the same active substance as the currently approved product.

• Moreover, the excipients, pH and osmolality have to be the same or, at least, comparable and should not interact with the drug substance (e.g. complex formation).

Parenteral solutions (EMEA 2009)

• In the case of other parenteral routes, e.g.

intramuscular or subcutaneous, and the test

product is of the same type of solution (aqueous

or oily), contains the same concentration of the

same active substance and the same excipients

in similar amounts as the medicinal product

currently approved, bioequivalence studies are

not required.

Oral solutions (EMEA 2009)

• If the test product is an aqueous oral solution at

time of administration and contains an active

substance in the same concentration as an

approved oral solution, bioequivalence studies

may be waived, if the excipients contained in it

do not affect gastrointestinal transit, absorption ,

solubility or in-vivo stability of the active

substance.

In vitro testing:

interpretation of results (EMEA 2009)

• In cases where more than 85% of the drug

is dissolved within 15 minutes, dissolution

profiles may be accepted as similar without

further mathematical evaluation, except in the

case of gastro-resistant formulations where

the dissolution takes place in the intestine and

the 15 minutes for gastric-emptying lacks of

physiological meaning

In vitro equivalence

• The disintegration vs. the

absorption phase

• The logic to support an in

vitro testing

– to waive in vivo study rather

than to demonstrate a

bioequivalence

In vitro testing (EMEA 2009)

• The results of in vitro dissolution tests at least at pH 1.2, 4.5, 6.8 and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported

In vitro testing: data analysis

• The similarity may be compared by model- independent or model-dependent methods e.g. by statistical multivariate comparison of the parameters of the Weibull function or the percentage dissolved at different time points, or by calculating a similarity factor e.g. the f2 similarity factor defined below.

• In this equation ƒ2 is the similarity factor, n is the number of time points, R (t) is the mean percent drug dissolved of e.g. a reference product, and T(t) is the mean percent drug dissolved of e.g. a test product

The Bioequivalence trial

• Selection of subjects

• Reference material

• Dose to be tested (single vs. multiple)

• Administration / Sampling

• Design

• The a priori Bioequivalence range

• The sample size

• Characteristics to be investigated

B2-Bioequivalence

trial :

test subjects

Bioequivalence : test subject

• Remind : B.E. trial is not to document

bioavailability variability

• The selected subjects must be as

homogeneous as possible (health status,

age, sex, weight)

Test subject (EMEA 2010)

Health status:

• The subject population for bioequivalence studies should be selected with the aim to permit detection of differences between pharmaceutical products.

• In order to reduce variability not related to differences between products, the studies should normally be performed in healthy volunteers unless the drug carries safety concerns that make this unethical.

• This model, in vivo healthy volunteers, is regarded adequate in most instances to detect formulation differences and the results will allow extrapolation to populations in which the reference product is approved (the elderly, children, patients with renal or liver impairment, etc.)

Test subject (EMEA 2009)

• In general, subjects should preferably be between 18 -55 years old and of weight within the normal range

• They are screened for suitability by means of clinical laboratory tests, an extensive review of medical history, and a comprehensive medical examination.

• Subjects could belong to either sex;

• Subjects should preferably be non-smokers and without a history of alcohol or drug abuse.

Sex, bioavailability and bioequivalence

Sex effectFrequent in human medicine because Body Weight is not considered for

dosage regimen!

A sex effect

AUC


Sex effectFrequent in human medicine because Body Weight is not considered !

A B

A B

BE

Un effet sexe (ou tout autre effet comme ceux liés à l’âge, l’état de santé…) relatif à un

médicament n’est pas un problème pour la démonstration d’une BE ; ce qui poserait

problème serait une interaction entre l’un de ces effets et la formulation


Interaction sex * formulation

(A vs. B)

A B

A

B

BE

not BE

Les 2 formulations sont BE chez la femme mais pas chez

l’homme; il y a donc une interaction sexe*formulation


• Question: do we need to test both sexes?

–Bioavailability

Yes : possible sex effect frequent in human

medicine because BW is not taken into account

for dosage regimen

–Bioequivalence

No : interaction formulation*sex unlikely

see: Chen ML et al Pharmacokinetic analysis of bioequivalence

trials: implication for sex related issues in clinical pharmacology

and biopharmaceutics. Clin. Pharmacol. 2000, 68: 510-521

Gender representation in trials

• US congress enacts legislation to require

that a clinical trial must be “designed and

carried out in a manner sufficient to provide

for a valid analysis of whether the variables

being studied in the trial affect women…

differently than other subjects in the trial”

Reference material in Bioequivalence(Guideline EMEA 2009)

• the chosen reference medicinal product must be a

medicinal product authorised in the Community, on the

basis of a complete dossier in accordance with the

provisions of Article 8 of Directive 2001/83/EC, as

amended.

• The product used as reference product in the

bioequivalence study should be part of the global

marketing authorisation of the reference medicinal

product.

• The choice of the reference medicinal product should

be justified by the applicant.

B3- Dose à tester

Dose to be tested

• The approved dose must be tested

• For drugs with multiple claims

involving different doses, different trials

should be performed

Single dose vs. multiple

doses

steady state studies

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 50 100 150 200 250 300

Time (h)

1

2

K01=0.1 vs. 0.05h-1 single dose administration

Formulation1

FFormulation

2ormulation2

Formulation2

0.0

0.5

1.0

1.5

2.0

2.5

0 50 100 150 200 250 300

Time (h)

1

2

K01=0.1 vs 0.05h-1. Multiple doses administrations

Formulation2

Formulation1

Single dose vs. multiple dose steady state studies

2 products that are not bioequivalent after a single dose may appears to be bioequivalent in a multiple dose administration

Design: Standardisation (EMEA 2009)

– The test conditions should be standardised in

order to minimise the variability of all factors

involved except that of the products being

tested.

– Therefore, it is recommended to standardise

diet, fluid intake and exercise

Fasting or fed conditions (EMEA 2009)

• The study should be conducted during fasting conditions unless the SPC recommends intake of the originator product only in the fed state.

– If the recommendation of food intake in the SPC is based on pharmacokinetic properties such as higher bioavailability, the bioequivalence study should be conducted in the fed state.

– Also if the recommendation of food intake is intended to decrease adverse events or to improve tolerability, it is recommended to conduct the bioequivalence study in fed state, although a bioequivalence study under fasting conditions could be acceptable if this has been adequately justified.

1- Before drug administration to assess absence

of assay interference or possible carryover

2- Single dose study :

• about 10 samples

• adequate to characterize absorption (before Tmax)

• up until the LOQ

• 4-5 terminal half-life after Tmax

3- Multiple dose study

• 10 samples during the dosing interval

Bioequivalence : Blood sampling

B4-Bioequivalence :

Experimental design

Bioequivalence:

experimental design

• Parallel design

• Cross-over design

Parallel design

subjects

Group 1Formulation 1

Group 2 Formulation 2

Randomly assigned to treatments

Example: - growing animals- small animals (fish, chicken,…) (blood sampling)- long half-life (washout)

Groups and formulations are confounded

- Advantage

• no washout period (appropriate for long - acting drug )

• possible unequal numbers of subjects per treatment

group

• statistical analysis is still possible when subjects (animals)

are lost during the experiment

- Limits

• more subjects are required

Bioequivalence : Parallel design

Bioequivalence: parallel design

• Drug with very long terminal t1/2

- 2x2 crossover

- other crossover

e.g. : AB, BA, AA, BB ( BALAAM design )

Bioequivalence : experimental design

1 2

1

2 A

BA

B

groupsor

sequences

periods

Bioequivalence : 2x2 crossover design (I)

• Advantage

• decrease in the residual error, therefore

reduction in the number of subjects

• Limits

• washout period required

• risk of an unequal carryover effect

• difficulties in analyzing the design if

subjects are lost during the experiment

B5-Bioequivalence :The a priori

Bioequivalence range

A priori Bioequivalence range

•These are the two limits ( 1, 2 ) between

which the 90 % CI interval of the ratio of

the two product should be located in order

to accept average B.E.

•To be defined by the clinician

Acceptance limits (EMEA 2009)

• In studies to determine bioequivalence after a single dose, the parameters to be analysed are AUCt and Cmax

• For these parameters the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of 80-125%.

– Confidence intervals should be presented to two decimal places. To be inside the acceptance interval the lower bound should be ≥ 80.00 and the upper bound should be ≤ 125.00.

the 90 % CI of the ratio

BE accepted

1 2

Decision procedures in bioequivalence trials

80%+125%

µT / µRRatio of test and reference formulation

BE not accepted

BE not accepted

C’est l’Intervalle de confiance du rapport des AUC qui doit être entre les bornes et non le rapport

lui même et sauf à prendre un nombre de sujets très grand, on ne peut pas imaginer que 2

formulations qui seraient réellement différentes de 15-20% puissent être déclarées BE.

L’intervalle ce confiance du ratio doit être

intégralement contenu dans l’intervalle

d’équivalence 0.80-1.25

A priori Bioequivalence range (4)

• For drug with a narrow therapeutic index

0.90 - 1.10 (additive model)

0.90 - 1.11 (multiplicative model)

B6-Bioequivalence sample size

Bioequivalence : sample size (I)

• The number of subjects has not to be

justified if the appropriate risk is

controlled (consumer risk, 5 %)

• For economical and ethical reasons,

the appropriate number of subjects

must be calculated to avoid an

excessively high producer risk

Bioequivalence : sample size (II)Information required to calculate the sample size

: The bioequivalence range ( ± 20 % )

: The consumer risk (5 % )

: The producer risk (e.g., 20 % )

( the probability of rejecting bioequivalence

when products are actually bioequivalent.

Power is used only in planning the

experiment, not as part of the statistical test )

: The error / (residual) variance

Bioequivalence : sample size :multiplicative model

T / R

0.90 1.0 1.10

12

38

80

CV %

exp (2) - 1

10

20

30

6.0

16

32

10

32

68

= 5 % - Power 80 %

1 = 0.80 2 = 1.25

Pour 2 formulations qui diffèreraient réellement de 10% (-10%), il faudrait faire un essais enrôlant 80

sujets pour démontrer une BE si le CV% de la résiduelle est de 30%

Nombre de sujets nécessaires:

Cas du lévothyrox

• Large residual error is likely

B8-Bioequivalence :

Characteristics to be investigated

- AUC & Cmax, (no longer Tmax)

- Others

- How to calculate or obtain these relevant

parameters

• Curve fitting vs trapezoidal rule

• Cmax: observed vs calculated

BE Characteristics to be investigated

B9-Bioequivalence :

Analytical techniques

Bioequivalence :analytical technique

• Must be validated

• Case of a chiral drug

•An enantioselective assay may have to be

used

• Pooled approach as a preliminary analysis

Statistical analysis

• The test problem

• Data analysis

-Distribution

- Outliers

- Logarithmic transformation

- 2 x 2 crossover / the carryover effect

- Parametric vs. non-parametric

The test problem

Bioequivalence : the test problem

From a regulatory point of view the

producer risk of erroneously rejecting

bioequivalence is of no importance

The primary concern is the protection of

the patient (consumer risk) against the

acceptance of BE if it does not hold true

H 0 : T - R =


Classical test of null hypothesis (I)

H 1 : T - R

T and R : population mean for test and

reference formulation respectively

Decision on the BE cannot be based on the

classical null hypothesis

or T = R

or T R

Classical statistical hypothesis: drawback

F% Ref Testn=1000 n=1000

100

702

Statistically different for p 0.05 but actually therapeutically equivalent

652

Classical statistical problem : the drawback

F% Ref Testn=3 n=3100

70

30

0

Not statistically different with p ≥ 0.05 but actually not therapeutically equivalent


Classical test of null hypothesis

• Acceptance of B.E. despite clinically relevant

difference between R and T formulation

• Can be totally misleading

• Rejection of B.E. despite clinically irrelevant

difference between R and T

Bioequivalence : the test problemClassical test of null hypothesis

Use of the classical null hypothesis would

encourage poor trials, with few subjects,

under uncontrolled conditions to answer

an irrelevant question

Bioequivalence: the test problem

• The appropriate hypothesis

H01(Ref -test)

H02(Ref -test)

Observation

H0

H1(Ref -test)

q1 q2

q2q1 inequivalent

equivalent

Bioequivalence: the test problem

• The appropriate hypothesis

(Ref -test)

q1 q2

H01 H02

two unilateral "t" tests

Can we reject H01? Can we also reject H02?

YESBioequivalent

YES

5% 5%

Bioequivalence : the test problemThe two one-sided test procedure

t 1 - ( )(XT - XR) - 1

s 2 / n

t1 =

(XT - XR)

s 2 / n

t 1 - ( )2 -

=t2

s : square root of the error mean square (ANOVA)

n : number of subjects

: df associated with s

only the 90 % CI

(administrativebioinequivalence)

Conclusion :BE rejected

BE accepted

BE accepted

the 90 and 95% CI

BiologicalBioinequivalence

BiologicalBioinequivalence

No conclusion (Lack of power for any decision)

Industrial point of view

Regulatory point of view1 A priori B.E. Range 2

Decision procedures in bioequivalence trials

Pharmacometric issues

The 2x2 cross-over design

the carryover effect

The carryover effect

• The direct drug effect is the effect that

a drug produces during the period in

which the drug is administered

• The carryover effect is the drug effect

that persists after the end of the dosing

period ("memory effect")


If the carryover effects are unequal,

no unbiased estimate exists for the

direct effects from both periods


• The washout period is the rest period

between 2 treatment periods

• The duration depends on the drug

• Should be long enough to avoid a

carryover effect

Origin: a too short washout period

Equal vs. unequal cary-over effect

Period 1 Period 2

A B

B A

Period 1 Period 2

A B

B A

Equal carryover

effect give a period

effect

Unequal carry-over effect give

a sequence effect that is

totally confounded in a 2x2

crossover design with a

formulation-by-period

interaction

Conclusions (1)

1.Personne ne conteste globalement l’intérêt des génériques

2.Ce n’est pas une raison pour ne pas se poser certaines questions à la fois techniques et médico-légales ou encore de discréditer les curieux en les accusant d’être liés à un lobby

3.Comme toute décision faisant intervenir des intérêts compétitifs, la politique relative aux modalités d’usage des génériques devrait se faire dans le cadre d’une analyse de risques:

• appréciation du risque (les aspects scientifiques et techniques de la démonstration de la BE)

• gestion du risque (le droit de substitution)

• communication sur le risque (et non de la propagande)

Conclusions (2)

1. Aspects techniques• Sont généralement justifiés pour démontrer une BE:

• L’approche pharmacocinétique plutôt que pharmacodynamique et clinique

• Le choix de volontaires sains plutôt que des patients– Sauf si on suspecte une interaction formulation*type de sujet

• La dose unique plutôt que des doses multiples

• Le nombre de sujets, même faible, si le risque statistique approprié (celui du patient) est contrôlé

• Sont discutables et méritent d’être discuté:• La non démonstration statistique de la « substituabilité »

(switchability) des formulations (princeps vs. génériques et génériques entre eux)

• Le choix, a priori, des intervalles d’équivalence qui doit rester une décision médicale prise dans l’intérêt du patient

• Le foisonnement en France des génériques et la fixation du risque de première espèce à 5%

Conclusions (3)

2-Aspects de gestion du risque

• Est discutable et mérite d’être discutée la politique

française de substitution• Pour certains types de médicaments à marges thérapeutiques

étroites (anti-épileptiques, anti-arythmiques….,) ou encore

pour les populations à risque, le prescripteur devrait être le

décideur par défaut

3-Les aspects industriels/BPF

• Les contrôles dans certains pays (Chine, Inde,

Brésil..)

4-Tout ce qui tourne autour de l’observance et de la

pharmacovigilance

a-bioéquivalence: considérations techniques et

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