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NATIONAL
VETERINARY
SCHOOL
TOULOUSE
Bioéquivalence & génériques:
Science et Polémiques
PL Toutain
Ecole Nationale Vétérinaire de Toulouse, France
Update June 2010
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[PHENYTOIN]
µg/mL
Change in phenytoin excipients results in
epidemic toxicity
WEEKS
* Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70
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Le site de L’EMA
Nouvelle ligne directrice adoptée en 2010
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Bioequivalence: EMA
– Guideline on the investigation of
bioequivalence (2009) (Draft)
• This guideline defines when bioequivalence studies are
necessary and formulates requirements for their design,
conduct, and evaluation.
• The guideline focuses primarily on bioequivalence for
immediate release dosage forms with systemic action.
– Questions & Answers on the Bioavailability and
Bioequivalence Guideline London, 27 July 2006
• Doc Ref: EMEA/CHMP/EWP/40326/2006
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Guideline on the investigation of
bioequivalence: other guidelines
• Specific recommendations regarding bioequivalence
studies for modified release products, transdermal
products and orally inhaled products are given in
other guidelines
• Recommendation for the comparison of biologicals to
reference medicinal products can be found in
guidelines on biosimilar products.
• Recommendations for pharmacokinetics of
therapeutic proteins are also described in a specific
guideline (CPMP/EWP/89249/04)
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Bioequivalence: FDA
Guidance for Industry
Statistical Approaches to
Establishing Bioequivalence
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2001
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Les génériques
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Définition légale du générique
(Directive 2001/83/EC, Article 10(2)(b))
• Une définition légale a été introduite dans le Code de
la Santé Publique depuis 1996 (article L.5121-1 CSP) :
•
on entend par spécialité générique d'une autre spécialité,
une spécialité qui a la même composition qualitative et
quantitative en principes actifs, la même forme
pharmaceutique, et dont la bioéquivalence avec la
spécialité de référence a été démontrée par des études
appropriées de biodisponibilité.
• Possibilité de différence s dans la composition
excipiendaire
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Marché des génériques en volume et en valeur
en 2006 (LEEM)
•
Pour les médicaments génériqués, les génériques dépassent les princeps .
Les génériques ont permis à la Sécurité Sociale de réaliser une économie
d’un milliard d’euros en 2008
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Parts de marché des génériques aux US
Proportion des dépenses (%)
Proportion des prescriptions (%)
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Pharmaceuticals
– Justification of high prices
•
•
•
•
High risk industry
Must ensure investment return
High cost of raw materials
Must ensure companies have funds to
invest in R&D to bring new and
innovative life saving products for all of
humanity
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Foisonnement actuel des génériques
• Environ 800 dossiers de génériques sont déposés
chaque année à l'AFSSAPS, soit 3 par jour ouvrable.
• En 2008, sur 519 AMM délivrées en France, 467
concernaient des génériques, soit 90% des AMM.
• À l'échelle européenne, 65 % des demandes déposées
en 2008 concernaient des génériques
Question: combien y a-t-il de génériques vraiment différents pour une
spécialité donnée de référence?
(distinction entre génériques issus de différentes firmes de simples
copies conformes ou seule l’étiquette change)
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Foisonnement actuel des génériques :
les problèmes
1. Quid de la substitution entre génériques
2. Quid du risque nominal de 5% qui est retenu
dans les études de BE
3. Quid des effets de la diminution des prix sur la
consommation et la surconsommation de
médicament
4. Quid de la traçabilité, de la pharmacovigilance
(effet de dilution de l’info?) etc.
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Le répertoire des génériques
• Le répertoire des génériques, créé et géré par
l’Afssaps, est constitué par les groupes
génériques représentant le médicament
princeps et ses génériques – commercialisés ou
non-.
• En 2007 il représente 2,9 milliards d’euros de
chiffre d’affaires (1,1 milliard pour les princeps et
1,8 milliard pour les génériques) soit près de
16% du marché remboursable
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Influence du nombre de génériques sur le
marché sur le prix du générique (US)
Est-ce une bonne nouvelle ou un facteur possible de surconsommation
des médicaments? Le cas des antibiotiques
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In: Clinical infectious deseases 2005 41 114-117
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Correlation between community use and the
number of trade names for oral-use agents for 6
antibacterial classes in EU
High consumption countries
Nb of trade names
Low consumption countries
Nb of trade names
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Generics and antibiotic consumption
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The objective of this survey was
to evaluate, in a community setting,
the effect of price on consumption
of ciprofloxacin and on ciprofloxacin
resistance in Escherichia coli urine
isolates
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Number of ciprofloxacin trade names (black line)
and the median price per DDD (red line) and the
influence of the introduction of generics
Generics
Number of
trade names
Price
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The influence of the introduction of generics on the
total use of ciprofloxacin (black line) and median
price per DDD (red line)
Consumption
Generics
price
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Trends in the frequency of ciprofloxacin resistance among
E. coli urine (brown line) and the consumption of
ciprofloxacin (black line) from 1995 to 2005
Resistance
Consumption
Generics
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Conclusion
• After the introduction of generic ciprofloxacin, a
significant increase in the total consumption of
oral ciprofloxacin was observed in Denmark.
• The increase in consumption was significantly
correlated with ciprofloxacin resistance in E. coli
obtained from urine isolates
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Generic competition for drugs
availability:
Is it a good medicinal practice to
encourage the use of old
antibiotics rather new ones?
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Is it a good medicinal practice to encourage the
use of old antibiotics rather new ones?
• Traditionally, from a public health perspective, it
was encouraged not to employ newer drugs, but
rather to use the older antibiotics.
• The recommendation whether to choose older
rather than newer antibiotics was recently
challenged on an epidemiological basis
(Amyes et al., 2007) and shown to be flawed
for quinolones, cephalosporins and
carbapenems.
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For three antibiotic classes (quinolones, cephalosporins
and carbapenems), it was observed that the less active
drugs could be worse at hastening the spread of
resistance than more active drugs in the same class.
This led the authors to qualify the (WHO) stratagem of
recommending the use of old antibiotics as part of
microbiological folklore.
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La montée des critiques adressées aux
génériques
• Publications dans la littérature scientifique
–
–
–
–
–
Anti-épileptiques
Cyclosporine
Psychotropes
Antibiotiques
…….
• Opinion des prescripteurs (le testimonial)
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The case of cyclosporine
• A meeting of 14 transplant and pharmacokinetic specialists from Europe and North
America was convened in November 2001 to evaluate scientific and clinical data
regarding the use of different formulations of cyclosporin A (CsA).
• The following consensus was achieved. (1) CsA is a critical-dose drug with a
narrow therapeutic window. Clinical outcomes after transplantation are affected by
the pharmacokinetic properties of CsA, particularly by its bioavailability, and by
intrapatient variability in CsA exposure. (2) Standard bioequivalence criteria do not
address differences in CsA pharmacokinetics between transplant recipients and
healthy volunteers, or between subpopulations of transplant recipients. (3) In some
circumstances, currently available formulations of CsA that meet standard
bioequivalence criteria are likely to be nonequivalent with respect to
pharmacokinetic characteristics. (4) The choice of CsA formulation can affect the
short- and long-term clinical outcome.
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Le cas des anti-épileptiques
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Le cas des anti-épileptiques:
remise en cause de la substitution
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Le cas des anti-épileptiques :
la réponse de l’AFSSAPS
Rem: le principe de
précaution n’a pas été
invoqué pour cette question
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La communication de
l’assurance maladie
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Le médicament générique est la copie
exacte du médicament de marque
(Site Web de l’assurance maladie)
La communication de l’AM est militante
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Le cas des antiépileptiques (1)
• Comme suite à la publication d'un communiqué de la
Ligue Française Contre l'Epilepsie le 3 juillet 2007,
prenant position contre la substitution entre les
générique d’ antiépileptiques, l'AFSSAPS a mené une
enquête de pharmacovigilance et a interrogé les autres
agences de santé européennes.
• Au terme de cette enquête, il semble que la substitution
princeps/générique soit un facteur qui mérite une
attention notamment pour l'acide valproïque et la
lamotrigine.
• Dans le cas de la lamotrigine, on dénombre entre 20 et
40 notifications d'événements graves pour 100 000
patient-années sur la période contre 191,1 pour le
générique de Sandoz.
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Le cas des antiépileptiques (2)
• Les résultats de l'interrogation des agences européennes ont été
présentés par l'Unité de pharmacovigilance.
• Parmi les 18 pays ayant répondu aux infofax adressés par
l'AFSSAPS en avril et octobre 2007, 8 pays ont pris des mesures
concernant les médicaments génériques antiépileptiques.
– La Belgique et le Danemark ont décidé de réduire les bornes de
l'intervalle d'équivalence.
– Six pays ont interdit (Espagne, Finlande, Slovénie, Suède) ou encadré
(Norvège, Slovaquie) la substitution de médicaments antiépileptiques
par des génériques.
• Malgré la demande de l'Unité, les raisons ayant conduit à ces
différentes prises de position n'ont pas pu être obtenues. Les
impacts des différentes mesures prises ne sont pas connus non
plus.
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The case of antiepileptic drugs
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Autres signaux faibles: taux de
retour à l’original
Le taux de retour au princeps après substitution est plus important avec certains
antiépileptiques comme la lamotrigine (12.9%) qu’avec des antidépresseur et des
antihyperlipidémiques (1.5 -2.9%)
Etude financée par Glaxo
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Une revue récente faisant le point sur les
génériques d’antiépileptiques
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Le cas des antiépileptiques:
conclusions
1. Ce qui est contesté c’est la substitution, pas le
générique
2. Pas d’évidences fortes de problème biologique
3. probablement d’origine psychologique
d’appréhension à la substitution
4. Cas des vielles substances (Phénytoïne,
carbamazépine)
•
La PHT a une cinétique NL
5. Respecter le droit du patient de non substitution
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France-Soir du 24 janvier 2009
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Y. Juillières, L. Merle, F. Claudot, P. Lechat. Modérateurs : C. Ziccarelli, N. Danchin.
Séance "Point de vue" lors des XIXes Journées Européennes de la Société
Française de Cardiologie (Paris, 14-17 janvier 2009). "Les génériques en
cardiologie, un bienfait pour qui ?
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Y a-t-il des évidences cliniques
contre l’usage des génériques
• Clinical Equivalence of
Generic and Brand-Name
Drugs Used in cardiovascular
Disease: a systematic review
and meta-analysis.
• Kesselheim et al.
JAMA.2008; 300: 2514-2526.
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Clinical equivalence of generic and brand-name
drugs used in cardiovascular disease: a
systematic review and meta-analysis
• Objective: To summarize clinical evidence
comparing generic and brand-name drugs used in
cardiovascular disease and to assess the
perspectives of editorialists on this issue
• Sources: Systematic searches of peer-reviewed
publications in MEDLINE, EMBASE, and
International Pharmaceutical Abstracts from
January 1984 to August 2008
JAMA. 2008 Dec 3;300(21):2514-26
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Clinical equivalence of generic and brand-name drugs
used in cardiovascular disease: a systematic review
and meta-analysis
• It was identified 47 articles covering 9 subclasses of cardiovascular
medications, of which 38 (81%) were randomized controlled trials
(RCTs).
• Clinical equivalence was noted in:
–
–
–
–
–
–
7 of 7 RCTs (100%) of beta-blockers,
10 of 11 RCTs (91%) of diuretics,
5 of 7 RCTs (71%) of calcium channel blockers,
3 of 3 RCTs (100%) of antiplatelet agents,
2 of 2 RCTs (100%) of statins,
1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1
of 1 RCT (100%) of alpha-blockers.
• Among narrow therapeutic index drugs, clinical equivalence was
reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents
and 5 of 5 RCTs (100%) of warfarin.
JAMA. 2008 Dec 3;300(21):2514-26
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Clinical equivalence of generic and brand-name drugs used in
cardiovascular disease: a systematic review and meta-analysis
•
•
•
These data suggest no evidence of superiority of brand-name to generic drugs in measured clinical
outcome among these studies
Effect sizes compare the difference in effect between the study groups difference divided by the SD of
this difference
It was considered that an effect size of less than 0.2 was very small, an effect size of 0.2 to 0.5 was
small and an effect size of 0.5 to 0.8 was medium.
JAMA. 2008 Dec 3;300(21):2514-26
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Clinical equivalence of generic and brand-name drugs
used in cardiovascular disease: a systematic review
and meta-analysis
• Aggregate effect size (n = 837) was -0.03
(95% confidence interval, -0.15 to 0.08),
indicating no evidence of superiority of
brand-name to generic drugs.
•
•
Effect sizes compare the difference in effect between the study groups difference divided by the
SD of this difference
It was considered that an effect size of less than 0.2 was very small, an effect size of 0.2 to 0.5
was small and an effect size of 0.5 to 0.8 was medium
JAMA. 2008 Dec 3;300(21):2514-26.
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Clinical equivalence of generic and brand-name drugs
used in cardiovascular disease: a systematic review
and meta-analysis
• Among 43 editorials, 23 (53%) expressed a negative view of the
interchangeability of generic drugs compared to 12 (28%) that
encouraged substitution of generic drug (the remaining 8 did not
reach a conclusion on interchangeability).
•
•
Rem : dans leur résumé (qui généralement est repris) les auteurs disent”
“Among 43 editorials, 23 (53%) expressed a negative view of generic drug
substitution” ce qui n’est pas synonyme de ce qui est dit dans la section résultats
c’est à dire: “expressed a negative view of the interchangeability of generic drugs”
•
[on peut être favorable au principe de la substitution (opinion de gestionnaire) tout
en émettant des réserves à caractère scientifique sur les preuves actuellement
manquantes sur la substituabilité des génériques entre eux et sur le fait que ce qui
est actuellement demandé dans les dossiers est une bioéquivalence moyenne et
non une bioéquivalence individuelle ]
JAMA. 2008 Dec 3;300(21):2514-26.
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Clinical equivalence of generic and brand-name drugs
used in cardiovascular disease: a systematic review
and meta-analysis
•
CONCLUSIONS: Whereas evidence does not
support the notion that brand-name drugs used in
cardiovascular disease are superior to generic
drugs, a substantial number of editorials counsel
against the interchangeability of generic drugs.
JAMA. 2008 Dec 3;300(21):2514-26.
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Critiques possibles des études de la
méta-analyse du JAMA
•
les études considérées dans la méta-analyse du JAMA sont généralement
des études conduites avec de faibles effectifs de sujets
– ce sont pour la moitié d’entre-elles des études de bioéquivalence dans lesquelles
ont également été mesurés des effets dont la plupart sont des critères de
substitution (type diurèse, TA, FC…) plutôt que des réponses cliniques d’intérêt
(mesures faites sur des volontaires sains)
•
Importance de la formulation de la question pour remettre en perspective
les conclusions d’une étude de méta-analyse:
– supériorité des princeps,
– équivalence clinique des princeps et des génériques
– non infériorité des génériques
•
Sont 3 types de questions qui n’appellent pas forcément les mêmes
conclusions
• Exemple: Dans un essai clinique, conclure à la non supériorité d’un traitement A contre
un traitement B ne veut pas dire que A et B sont équivalents!!
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A-Bioéquivalence:
considérations techniques et
scientifiques
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Les points de la présentation
1. Les génériques
2. Les aspects critiqués ou critiquables dans la démonstration d’une BE
• La définition EMEA de la BE: science & juridisme
• Le choix des études de biodisponibilité pour démontrer une BE:
•
•
est-ce acceptable? Quelles en sont les limites?
Pourquoi ne pas utiliser des effets plutôt que des concentrations plasmatiques ou
encore des essais cliniques pour démontrer une BE?
• Que démontre-t-on réellement dans une étude de BE?
•
La « substituabilité » (switchability) est-elle démontrée?
• Le foisonnement des génériques et « substituabilité »
• Le choix de volontaires sains plutôt que de patients pour démontrer la BE est-il
acceptable?
• La démonstration d’une BE avec une dose unique est-elle acceptable?
• L’intervalle d ’équivalence a priori de 80-125%
•
•
Que veut-il dire exactement
Est-il suffisamment conservatoire?
• Les autres critiques portées sur les génériques
• Qualité pharmaceutique et inspections; excipients à effets notoires; packaging;
observance liée au caractères organoleptiques etc.
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A1-Bioequivalence :
Definition and assumptions
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Bioequivalence : Definition 2009 (I)
• Definition 2009
• Two medicinal products containing the same active
substance are considered bioequivalent if 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
• Definition 2001
– Two medicinal products are bioequivalent if their
bioavailabilities (rate and extent) after administration in
the same molar dose are similar to such degree that
their effect and safety will be essentially the same
•Glissement sémantique dans la définition qui est moins ambitieuse sur
le plan biologique mais probablement plus satisfaisante pour un juriste
•Une affirmation ne fait pas une définition
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Guideline on the investigation of
bioequivalence (2009)
• For generic applications, the purpose of
establishing bioequivalence is to
demonstrate equivalence in
biopharmaceutic quality between the
generic product and a reference
medicinal product in order to allow
bridging of clinical data associated with
the reference medicinal product.
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Equivalence in biopharmaceutic quality
man is viewed as a HPLC walking column
A
?
=
B
injection
Analytical approach in vivo approach
injection
HPLC column
Pharmaceutical equivalence
In vivo equivalence
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A2-Pourquoi le plasma pour
démontrer la bioéquivalence?
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Bioequivalence :
The basic assumption
• “Similar” overall plasma exposure
 same effects
–is it always true ?
• Classical objections
–Plasma concentration is not
biophase concentration
–there is no (univocal) relationships
between exposure and effect !
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Basic assumption to bioequivalence
Is there an univocal relationship between
exposure and effect ?
DOSE
yes
Plasma concentrations
Effects
driven by plasma
concentrations
Yes
yes
yes
Effects
not driven by plasma
concentrations
Yes
Plasma concentrations
Yes/No ?
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A3-Pourquoi utiliser le
concept de biodisponibilité
pour démontrer une
bioéquivalence
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Basic assumption to bioequivalence
Similar plasma concentration profile  same effect ?
Why ?
Effect
Drug property (efficacy)
Effect =
Emax
Emax  Dose
ED50 + Dose
ED50
Dose
Hybrid substance and formulation properties
(Potency)
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Basic assumption to bioequivalence
Substance property
ED50 =
Clearance  EC50
Bioavailability
Formulation property
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Basic assumption to bioequivalence
• Similar plasma concentration profile 
same effect?
Effect =
substance properties
Emax  Dose
Clearance  EC50 + Dose
F%
Formulation properties
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Basic assumption to bioequivalence
• Similar plasma concentration  same effect?
• Comparison of 2 formulations of the same drug
Emax  Dose
Emax  Dose
Vs. Effect,test =
Effect, pioneer =
Clearance  EC50
Clearance  EC50
+ Dose
+ Dose
F,ref
F,test
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
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A4- Ne pas confondre essai de
bioéquivalence
et un essai de biodisponibilité
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Bioequivalence vs. Bioavailability (I)
- Bioavailability trials must document
influence of different factors on the rate
and extent of drug absorption
• age
• sex
• route of administration
• disease
• •••••
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Bioequivalence vs. Bioavailability (II)
- Bioequivalence trial is to characterize two
products (e.g. pioneer vs. generic) and not
two sets of subjects
- Bioequivalence trial is to guarantee the
switchability of two formulations
- In bioequivalence trials, the subjects serve
as "walking chromatographic columns"
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Bioequivalence vs. Bioavailability (III)
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
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Equivalence in biopharmaceutic quality
man is viewed as a HPLC walking column
A
?
=
B
injection
Analytical approach in vivo approach
injection
HPLC column
Pharmaceutical equivalence
In vivo equivalence
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Bioequivalence vs. Bioavailability (IV)
Inference from a trial
- 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
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Bioequivalence :
Factor of variability to control (I)
• Species
• B.E. of two formulations has to be demonstrated in
each species (interaction between formulation and
species is systematically hypothesized )
• Food interactions
• This factor of variability addresses questions essentially
related to the pharmaceutical form and not related to the
future patient population
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A5-Does essentially the same
plasma time curve leads to
essentially the
same effect whether toxic or
therapeutic?
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Effect
PK/PD relationship to discuss
bioequivalence acceptance criteria
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
∆ = 20%
Exposure
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Effect
PK/PD relationship to discuss
bioequivalence acceptance criteria
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
∆ = 20%
Exposure
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Does essentially the same
plasma time curve leads to essentially the
same effect whether toxic or therapeutic?
Effects
identical
±40%
very
different
Systemic exposure
AUC
±20%
±20% Master pro 24 Fev 2010 - 77
Différence de biodisponibilité entre les
génériques et le princeps
• Enquête de la FDA
– Sur environ 224 génériques approuvés après 1962,
la différence a été de 3.5%
– Sur 127 bioéquivalences examinées en 1997 les
différences moyennes ont été:
• AUC: 3.25±2.97%,
• Cmax: 4.29±3.72%
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A6-Les différents définitions
statistiques possibles d’ une
bioéquivalence
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Average
vs.
population bioequivalence
vs.
individual bioequivalence
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Different types of bioequivalence
• Average (ABE) : mean
• Population (PBE) : prescriptability
• Individual (IBE) : switchability
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FDA: Guidance Update:
Average, Population, and
Individual Approaches to
Establishing Bioequivalence
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Average bioequivalence
• Test and reference are
bioequivalent if the means are
“sufficiently similar” with regard to
AUC and Cmax
• Sufficiently similar
– 0.80  µT / µR  1.25
–log scale log (0.8)  µT - µR  log (1.25)
Master pro 24 Fev 2010
- 83
Average bioequivalence
reference
test
AUC/ Cmax
Same mean
Master pro 24 Fev 2010
- 84
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)
Master pro 24 Fev 2010
- 85
Average bioequivalence
• Addresses only mean (center of
distribution) but not variability
(shape of distribution)
• Does not address switchability
Master pro 24 Fev 2010
- 86
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
Master pro 24 Fev 2010
- 87
Population bioequivalence
AUC distribution
Yes
No
“Test” and “reference” are bioequivalent if the entire
population distribution (mean and variability) are sufficiently
similar with regard to AUC and Cmax
Master pro 24 Fev 2010
- 88
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.
Master pro 24 Fev 2010
- 89
Individual bioequivalence
test
patient-by-formulation
interaction
YES
reference
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
Master pro 24 Fev 2010
- 90
Individual bioequivalence
• The clinical relevance of a subject-byformulation 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)
Master pro 24 Fev 2010
- 91
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
Master pro 24 Fev 2010
- 92
Switchability between generics
Master pro 24 Fev 2010
- 93
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.
Master pro 24 Fev 2010
- 94
Le droit de substitution:
un droit au quiproquo?
• Les apothicaires se permettaient de
replacer le “quid” par le “quod”ce qui
est à l’origine de l’ordonnance pour
éviter les quiproquos
• Mot d'origine latine (latin médiéval). Il proviendrait de quid pro quod
(latin classique juridique signifiant « qui pour quoi ») signifiant « une
chose à la place d'une autre » ; l'expression appartenait originellement
au vocabulaire pharmaceutique qui nommait ainsi un médicament pris
ou donné à la place d'un autre.
Master pro 24 Fev 2010
- 95
?
Generic 2
Generic 1
yes
yes
?
yes
Pioneer
???
Generic 3
Other reference
medicinal product
Master pro 24 Fev 2010
- 96
Différence possible de biodisponibilité
entre les génériques
• Il est souvent rapporté que les différences entre
génériques peuvent aller de -20 à +25% (ou de -36 à
+56%, Table ronde no 7 des XXIIIes rencontres nationales
de pharmacologie clinique)
• En fait ce n’est pas la différence mais son intervalle de
confiance (IC) qu’il faut considérer comme devant être
situé dans l’IC de référence (voir plus loin)
Master pro 24 Fev 2010
- 97
Il existe des différences entre
génériques
Master pro 24 Fev 2010
- 98
Performance of FDA Criteria
• Survey of ANDA Applications (19962001)
• Evaluated distribution of Cmax and AUC
T/R mean ratios (point estimates)
Master pro 24 Fev 2010
- 99
40
Percent (%)
30
20
10
0
0.70
0.75
0.80
0.85
0.90
0.95
1.00
1.05
1.10
AUC Point Estimate (T/R)
1.15
1.20
1.25
1.30
Master pro 24 Fev 2010
- 100
30
Percent (%)
25
20
15
10
5
0
0.70
0.75
0.80
0.85
0.90
0.95
1.00
1.05
1.10
1.15
Cmax Point Estimate (T/R)
1.20
1.25
1.30
Master pro 24 Fev 2010
- 101
40
Highly Variable
40
Percent (%)
30
20
10
0
0.70 0.80 0.90 1.00 1.10 1.20 1.30
0.75 0.85 0.95 1.05 1.15 1.25
AUC Point Estimate (T/R)
30
20
10
0
0.70 0.80 0.90 1.00 1.10 1.20 1.30
0.75 0.85 0.95 1.05Master
1.15
1.25
pro 24 Fev 2010 - 102
AUC Point Estimate (T/R)
B-The Bioequivalence
trial
Master pro 24 Fev 2010
- 103
B1-Types of Bioequivalence
trials
Master pro 24 Fev 2010
- 104
Types of bioequivalence trial
Metabolite
PD1
Dose
abs
Drug
C (t)
PD2
Clinical
efficacy
Dissolution
Drug
in
urine
PK
in vitro
testing
.....
PD
Clinical
in vivo testing
Master pro 24 Fev 2010
- 105
The use of urinary data (EMEA 2009)
• The use of urinary excretion data as a surrogate for a
plasma concentration may be acceptable in determining
the extent of exposure in case it is not possible to
reliably measure the plasma concentration-time profile
of parent compound.
• However, the use of urinary data has to be carefully
justified when used to estimate peak exposure.
– If a reliable plasma Cmax can be determined, this should be
combined with urinary data on the extent of exposure for
assessing bioequivalence.
Master pro 24 Fev 2010
- 106
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
Master pro 24 Fev 2010
- 107
Types of bioequivalence trial in vivo :
metabolite plasma profile (II)
Systemic bioavailability can be measured accurately
using a metabolite time profile
Metabolite formation is secondary to absorption of the
parent drug and the metabolite plasma profile may be
unable to differentiate formulation differences in
absorption rate of the parent drug (Chen and Jackson,
1992)
Consequence : bioequivalence may be accepted
based on metabolite data and rejected based on
parent drug even though identical statistical criteria
are used
- 108
Master pro 24 Fev 2010
Pourquoi ne pas utiliser des
effets ou des essais cliniques
plutôt que des concentrations
plasmatiques pour démontrer
une BE?
Master pro 24 Fev 2010
- 109
Bioequivalence and
Pharmacodynamic endpoint
• In case bioequivalence cannot be demonstrated
using drug plasma concentrations, in exceptional
circumstances pharmacodynamic or clinical
endpoints may be needed.
• This situation is outside the scope of the
guideline on the investigation of bioequivalence
(EMEA, 2009) and the reader is referred to
therapeutic area specific guidelines.
Master pro 24 Fev 2010
- 110
Types of Bioequivalence trial
Pharmacodynamic endpoints
Test
Reference
Effect
100 %
Response A
50 %
T and R are not
bioequivalent
Systemic exposure
AUC
Master pro 24 Fev 2010
- 111
Types of Bioequivalence trial
Pharmacodynamic endpoints
Test
Reference
Effect
100 %
Response B
50 %
T and R are
bioequivalent
Systemic exposure
AUC
Master pro 24 Fev 2010
- 112
Types of Bioequivalence trial
Pharmacodynamic endpoints
Test
Reference
Effect
100 %
Response B
(e.g: a surrogate)
Response A
(e.g;of clinical interest)
50 %
T and R are not
bioequivalent
T and R are
bioequivalent
Systemic exposure
AUC
Master pro 24 Fev 2010
- 113
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
Master pro 24 Fev 2010
- 114
Pharmacological trial
No blood concentration
- yes
Systemically acting drug
Blood concentration
for highly variable drug
- very debatable
Locally acting drug
inhalation drug,
dermatological preparation
etc.
Master pro 24 Fev 2010 - 115
- yes
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
Master pro 24 Fev 2010
- 116
Type of Bioequivalence trial :
clinical trial
Generally, poor metrological performance
Master pro 24 Fev 2010
- 117
In-vitro dissolution tests
Master pro 24 Fev 2010
- 118
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
Master pro 24 Fev 2010
- 119
in vitro equivalence
- Measurement of dissolution rate
• apparatus / relevant medium
- Treatment of dissolution curves
• statistical approach (split-splot for replicate
measurement permits testing of differences in
level and shape)
• modelling (e.g. weibull) and calculation of the
mean dissolution time
Master pro 24 Fev 2010
- 120
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
Master pro 24 Fev 2010
- 121
In-vitro dissolution tests in support of
biowaiver of strengths (EMEA 2009)
• Appropriate in vitro dissolution should
confirm the adequacy of waiving additional
in vivo bioequivalence testing.
• in vitro dissolution should be demonstrated
within the applied product series, i.e.
between additional strengths and the
strength(s) used for bioequivalence testing,
and between additional strengths of the
applied product and corresponding
strengths of the reference product.
Master pro 24 Fev 2010
- 122
In vitro testing: data analysis
• The similarity may be compared by model- independent or modeldependent 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
Master pro 24 Fev 2010 - 123
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
Master pro 24 Fev 2010
- 124
B2-Bioequivalence
trial :
test subjects
Master pro 24 Fev 2010
- 125
Test subject (EMEA 2009):
• 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.)
Master pro 24 Fev 2010
- 126
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.
Master pro 24 Fev 2010
- 127
Bioequivalence : test subjects
• Some issues on the selection of test
subjects
–healthy or diseased subjects?
• Possible interaction between health
status and formulation?
–sex: both male and female?
Master pro 24 Fev 2010
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Bioequivalence : test subject
• Remind : B.E. trial is not to document
bioavailability variability
• The selected subjects must be as
homogeneous as possible (age, sex,
weight)
Master pro 24 Fev 2010
- 129
Sex, bioavailability and bioequivalence
A sex effect
AUC
Sex effect
Frequent in human medicine because Body Weight is not considered !
Master pro 24 Fev 2010
- 130
Sex, bioavailability and bioequivalence
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
A B
A B
BE
Sex effect
Frequent in human medicine because Body Weight is not considered !
Master pro 24 Fev 2010
- 131
Sex, bioavailability and bioequivalence
Les 2 formulations sont BE chez la femme mais pas chez
l’homme; il y a donc une interaction sexe*formulation
B
A B
BE
A
not BE
Interaction sex formulation
(A vs. B)
*
Master pro 24 Fev 2010
- 132
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
Master pro 24 Fev 2010
- 133
Ne pas confondre un effet (facteurs sexe,
âge, état de santé…) sur la réponse à un
médicament (ce qui est fréquent) avec
une interaction entre l’un de ces
facteurs et une formulation (ce qui
semble rarissime)
Pour cette raison le choix de volontaires
sains plutôt que de patients pour tester
une BE est justifié
Master pro 24 Fev 2010
- 134
Reasons to exclude females
(women) from a BE Trial
– Hormonal fluctuation during the cycle may
increase the intra subject variability
gastric pH metabolism etc
actually few evidence
– Safety issue (abortion, fetal damage,…)
• Conclusion of the FDA (1993): there is no regulatory
or scientific basis for routine exclusion of women for
BE trials
– see Chen ML et al Drug information Journal 1995,
29: 813-820
Master pro 24 Fev 2010
- 136
Reasons to exclude females
(women) from a BE Trial
• FDA - 1993: published a document entitled
“Guidelines for the study and evaluation of
gender differences in the clinical
evaluation of drugs”
– specific issue for BE trials
– politically correct
Master pro 24 Fev 2010
- 137
B3- Dose à tester
Master pro 24 Fev 2010
- 138
Dose to be tested
• The approved dose must be tested
• For drugs with multiple claims
involving different doses, different trials
should be performed
Master pro 24 Fev 2010
- 139
Single dose vs. multiple
doses
steady state studies
Master pro 24 Fev 2010
- 141
Single dose vs. multiple dose steady state studies:
Guideline on the investigation of bioequivalence (2009)
• In general, single dose studies will suffice.
•
However, in case of dose or time-dependent pharmacokinetics,
resulting in markedly higher concentrations at steady state than
expected from single dose data, a potential difference in AUC
between formulations may be larger at steady state than after single
dose.
•
Hence, a multiple dose study may be required in addition to the
single dose study to ensure that the products are bioequivalent
regarding AUC also at steady state.
Master pro 24 Fev 2010
- 142
Single dose vs. multiple dose
steady state studies
- Advantage of multiple dose B.E. studies
• Excessive intersubject variability: NO
• Analytical difficulty
• Absence of washout period
- Therapeutic Indications
• Action of the drug on steady state
concentration
• Time dependent kinetics
- Design and analysis
Master pro 24 Fev 2010
- 143
Single dose vs. multiple dose
steady state studies
•Two bio-inequivalent formulations (single
dose) may become bioequivalent in steadystate condition
Master pro 24 Fev 2010
- 144
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
K01=0.1 vs. 0.05h-1 single dose administration
0.7
Formulation1
0.6
0.5
Formulation2
FFormulation
2ormulation2
0.4
1
0.3
2
0.2
0.1
0.0
0
50
100
150
200
250
300
Time (h)
K01=0.1 vs 0.05h-1. Multiple doses administrations
2.5
Formulation1
2.0
1.5
1.0
1
2
Formulation2
0.5
0.0
0
50
100
150
Time (h)
200
250
300
Master pro 24 Fev 2010
- 145
Multiple-dose studies
• Monte-Carlo simulation (FDA)
–the probability of failing the BE test
dramatically decrease upon multipledose administration
–multiple dose studies generally not
recommended by FDA
–it is possible to conclude to BE for a
multiple dose administration whereas
the 2 products are not BE!
Master pro 24 Fev 2010
- 146
B4-Bioequivalence :
Experimental design
Master pro 24 Fev 2010
- 147
Bioequivalence:
experimental design
• Parallel design
• Cross-over design
Master pro 24 Fev 2010
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Parallel design
subjects
Group 1
Formulation 1
Randomly
assigned to
treatments
Group 2
Formulation 2
Groups and formulations are confounded
Example:
- growing animals
- small animals (fish, chicken,…) (blood sampling)
- long half-life (washout)
Master pro 24 Fev 2010
- 149
Bioequivalence : Parallel design
- 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
Master pro 24 Fev 2010
- 150
Bioequivalence: parallel design
• Drug with very long terminal t1/2
Master pro 24 Fev 2010
- 151
Bioequivalence :
experimental design
- 2x2 crossover
periods
groups
or
sequences
1
2
1
A
B
2
B
A
- other crossover
e.g. : AB, BA, AA, BB ( BALAAM design )
Master pro 24 Fev 2010
- 152
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
Master pro 24 Fev 2010
- 153
B5-Bioequivalence :
The a priori
Bioequivalence range
Master pro 24 Fev 2010
- 154
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
Master pro 24 Fev 2010
- 155
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.
Master pro 24 Fev 2010
- 156
Decision procedures in bioequivalence trials
BE not
accepted
1
80%

2
the 90 % CI of the ratio
BE accepted
BE not
accepted
+125%
µT / µR
Ratio of test and
reference formulation
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
Master pro
24 Fev 2010 - 157
formulations qui seraient réellement différentes de 15-20% puissent être déclarées
BE.
Intervalle de confiance vs.
Intervalle de tolérance
Master pro 24 Fev 2010
- 158
Confidence interval
• A Confidence interval is a range of values
which span from the Lower Confidence
Limit to the Upper Confidence Limit.
• We expect this range to encompass the
population parameter of interest, such as
the population mean, with a degree of
certainty which we specify
Master pro 24 Fev 2010
- 159
Tolerance interval
• The tolerance interval estimates the range which
should contain a certain percentage of each
individual measurement in the population.
•
Because tolerance intervals are based upon only a
sample of the entire population, we cannot be 100%
confident that that interval will contain the specified
proportion. Thus there are two different proportions
associated with the tolerance interval: a degree of
confidence, and a percent coverage. For instance,
we may be 95% confident that 95% of the population
will fall within the range specified by the tolerance
interval.
Master pro 24 Fev 2010
- 160
A priori Bioequivalence range (4)
• For drug with a narrow therapeutic index
0.90 - 1.10 (additive model)
0.90 - 1.11 (multiplicative model)
Master pro 24 Fev 2010
- 162
B6-Bioequivalence
sample size
Master pro 24 Fev 2010
- 163
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
Master pro 24 Fev 2010
- 164
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
Master pro 24 Fev 2010
- 165
Bioequivalence : sample size :
multiplicative model
 = 5 % - Power 80 %
1 = 0.80 2 = 1.25
T / R
CV %
exp (2) - 1
10
20
30
0.90
1.0
1.10
12
38
80
6.0
16
32
10
32
68
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% Master pro 24 Fev 2010 - 166
B8-Bioequivalence :
Characteristics to be
investigated
Master pro 24 Fev 2010
- 167
BE Characteristics to be investigated
- AUC & Cmax, (now not Tmax)
- Others
- How to calculate or obtain these relevant
parameters
• Curve fitting vs trapezoidal rule
• Cmax: observed vs calculated
Master pro 24 Fev 2010
- 168
B9-Bioequivalence :
Analytical techniques
Master pro 24 Fev 2010
- 169
Bioequivalence :
analytical technique
• Must be validated
• An enantioselective assay must be used
for a chiral drug
• Pooled approach as a preliminary analysis
Master pro 24 Fev 2010
- 170
Statistical analysis
• The test problem
• Data analysis
-Distribution
- Outliers
- Logarithmic transformation
- 2 x 2 crossover / the carryover effect
- Parametric vs. non-parametric
Master pro 24 Fev 2010
- 171
The test problem
Master pro 24 Fev 2010
- 172
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
Master pro 24 Fev 2010
- 173
Bioequivalence : the test problem
Classical test of null hypothesis (I)
H 0 : T - R = 
or T = R
H 1 : T - R  
or 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
Master pro 24 Fev 2010
- 174
Classical statistical hypothesis: drawback
F%
Ref
n=1000
Test
n=1000
100
702
652
Statistically different for p  0.05 but actually
therapeutically equivalent
Master pro 24 Fev 2010 - 175
Classical statistical problem : the drawback
F%
100
Ref
n=3
Test
n=3
70
30
0
Not statistically different for p  0.05 but
actually not therapeutically equivalent
Master pro 24 Fev 2010
- 176
Bioequivalence : the test problem
Classical test of null hypothesis
• Can be totally misleading
• Acceptance of B.E. despite clinically relevant
difference between R and T formulation
• Rejection of B.E. despite clinically irrelevant
difference between R and T
Master pro 24 Fev 2010
- 177
Bioequivalence : the test problem
Classical 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
Master pro 24 Fev 2010
- 178
Bioequivalence: the test problem
• The appropriate hypothesis
H01
(Ref -test)
H0
H02
(Ref -test)
q1
inequivalent
q2
equivalent
(Ref -test)
H1
Observation
q2
q1
Master pro 24 Fev 2010
- 179
Bioequivalence: the test problem
• The appropriate hypothesis
q2
q1
(Ref -test)
H01
5%
H02
5%
two unilateral "t" tests
Can we reject H01?
YES
Can we also reject H02?
Bioequivalent
YES
Master pro 24 Fev 2010
- 180
Bioequivalence : The test problem (2)
Multiplicative model (1)
Ho : µT / µR < 1 or µT / µR > 2 (Bioinequivalence)
H1 : 1 < µT / µR < 2 (B.E.)
µT and µR : the expected medians for test and reference
respectively
1 and 2 ( 0 <  < 1 < 2 ) : lower and upperlimits of the
bioequivalence range
(1 = 0.8, 2 = 1.25 )
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Bioequivalence : the test problem
The two one-sided test procedure
t1 =
(XT - XR) - 1
s
t2 =
t1-()
2/n
2 - (XT - XR)
s
t 1 -  ( )
2/n
s : square root of the error mean square (ANOVA)
n : number of animals
 : df associated with s
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Decision procedures in bioequivalence trials
Regulatory point of view
only the 90 % CI
1
A priori B.E. Range
2
BE accepted
Conclusion :BE rejected
(administrative
bioinequivalence)
Industrial point of view
BE accepted
the 90 and 95% CI
No conclusion
(Lack of power for any decision)
Biological
Bioinequivalence
Biological
Bioinequivalence
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Pharmacometric aspects
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Statistical analysis (EMEA 2009)
• The data should be transformed prior to
analysis using a logarithmic
transformation.
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Bioequivalence : statistical analysis
• Logarithmic transformation (1)
•To ensure additivity of the model
•To normalize distribution
•To stabilize the variance
•To express the confidence interval as a ratio to
avoid the use of XR to estimate µR to express 1
and 2
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Bioequivalence : statistical analysis
Logarithmic transformation :
parameter for central location
Median (geometric mean) = Exp Xe
( Xe : least square mean )
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Why to perform an ANOVA
• To validate the cross-over design
• To estimate the residual which is
required for the two one-sided
test procedures
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The 2x2 cross-over design
The period effect
• Not desirable
• Does not invalidate a cross-over design
• Origin : enzymatic induction,
environment, equal carryover
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The 2x2 cross-over design
The formulation effect
• Possible
• Does not invalidate the BE conclusions
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Une conclusion du type:
il y a une différence significative
entre le princeps et le générique
(p<0.05) mais les deux produits
sont bioéquivalents (P<0.05) est
tout à fait possible mais
difficilement compréhensible pour
de nombreux prescripteurs
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Crossover design
The statistical model
Yijkl = µ + Aij + k + l + i+ ijkl
Overall mean
Aij : Random effect of the jth subject wihin the ith sequence
k : Direct effect of the kth period
l : Direct effect of the lth formulation
i : Residual effect (or fixed carryover) of the ith formulation
from period 1 to period 2 (or effect of the ith sequence)
ijkl : Within subject random error term
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The 2x2 cross-over design
Yijkl = µ + Aij + k + l + i+ ijkl
Aij: Random effect of the j
th
subject wihin the ith
sequence
• mean : 0
• Variance : ²s
(²s is used to explain the intersubject
variability)
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The 2x2 cross-over design
Yijkl = µ + Aij + k + l + i+ ijkl
ijkl : Within subject random error term
mean : 0
• variance : ²e
(²e is used to assess the intrasubject)
if ²R = ²t = ²e
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ANOVA 2x2 cross-over
• Selection of the appropriate ratio :
the choice of the appropriate error term
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Bioequivalence : statistical analysis
crossover design
The ANOVA Table
Source
df
F ratio
denominator
Sequence
(group, order)
1
subject (SEQ)
Subject (SEQ) NTR + NTR - 2
residual
Period
1
residual
Formulation
1
residual
Residual
NTR + NTR - 2
Remark
test for differential
carryover ( = 0.1)
of no interest for B.E.
to calculate the CI
L’effet séquence n’est plus à tester dans la nouvelle
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ligne directrice
The 2x2 cross-over design
the carryover effect
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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")
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The carryover effect
If the carryover effects are unequal,
no unbiased estimate exists for the
direct effects from both periods
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The carryover effect
Origin: a too short washout period
• 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
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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
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The carryover effect (EMEA 2009)
• A test for carry-over should not be performed and no decisions
regarding the analysis (e.g. analysis of the first period, only) should
be made on the basis of such a test.
• The potential for carry-over can be directly addressed by
examination of the pre-treatment plasma concentrations in period
2 (and beyond if applicable).
• If there are any subjects for whom the pre-dose concentration is
greater than 5 percent of the Cmax value for the subject in that
period, the statistical analysis should be repeated with those
subjects excluded.
• Results from both analyses should be presented, but the analysis
with the subjects excluded should be considered as primary.
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Statistical analysis (EMEA 2009)
• The presentation of the findings of a bioequivalence
trial should include a 2x2-table that presents for
each sequence (in rows) and each period (in
columns) means, standard deviations and number
of observations for the observations in the respective
period of a sequence.
•
In addition, tests for difference and the respective
confidence intervals for the treatment effect, the
period effect, and the sequence effect should be
reported for descriptive assessment.
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Acceptance limits (EMEA 2009)
• In specific cases of products with a narrow
therapeutic range, the acceptance interval
may need to be tightened.
• Moreover, for highly variable drugs the
acceptance interval for Cmax may in
certain cases be widened .
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A priori Bioequivalence range for
drug with a narrow therapeutic index
0.90 - 1.10 (Untransformed)
0.90 - 1.11 (Ln-transformed)
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Bioequivalence
sample size
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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
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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
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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 médicolégales 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)
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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%
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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
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