a-bioéquivalence: considérations techniques et
TRANSCRIPT
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
Basic assumption to bioequivalence
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 =
Basic assumption to bioequivalence
Clearance EC50
Bioavailability
Substance property
Formulation property
• Similar plasma concentration profile
same effect?
Basic assumption to bioequivalence
Effect = Emax Dose
Clearance EC50 + Dose
F%
substance properties
Formulation properties
Basic assumption to bioequivalence
• 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 bioequivalence
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
Average bioequivalence
• 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.)
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, bioavailability and bioequivalence
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
Sex, bioavailability and bioequivalence
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
Sex, bioavailability and bioequivalence
• 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 =
Bioequivalence : the test problem
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
Bioequivalence : the test problem
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")
The carryover effect
If the carryover effects are unequal,
no unbiased estimate exists for the
direct effects from both periods
The carryover effect
• 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