bioéquivalence & génériques: s cience et polémiques
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Bioéquivalence & génériques: S cience et Polémiques. NATIONAL VETERINARY S C H O O L T O U L O U S E. PL Toutain Ecole Nationale Vétérinaire de Toulouse, France. Version du 3 février 2009. [ PHENYTOIN] µg/mL. WEEKS. Change in phenytoin excipients results in epidemic toxicity. - PowerPoint PPT PresentationTRANSCRIPT
Toulouse fac med 2009 - 1
Bioéquivalence & génériques:Science et Polémiques
NATIONALVETERINARYS C H O O L
T O U L O U S E
PL ToutainEcole Nationale Vétérinaire de Toulouse, France
Version du 3 février 2009
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Change in phenytoin excipients results in epidemic toxicity
[PH
EN
YT
OIN
]
µg
/mL
WEEKS
* Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70
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Bioequivalence: EMEA
– 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 IndustryStatistical Approaches to
Establishing Bioequivalence
U.S. Department of Health and Human ServicesFood 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.
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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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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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Evolution du marché des génériques en France
•
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Parts de marché des génériques aux US
Proportion des dépenses (%) Proportion des prescriptions (%)
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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 Low consumption countries
Nb of trade names Nb of trade names
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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 hioequivalence 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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Rem: le principe de précaution n’a pas été
invoqué pour cette question
Le cas des anti-épileptiques :la réponse de l’AFSSAPS
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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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The case of antiepileptic drugs
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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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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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Le blog d'Eric Gibert - DocCheck Blog
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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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• Definition (or rather a statement?) 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
Bioequivalence : Definition 2009 (I)
•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 qualityman is viewed as a HPLC walking column
?=A B
Analytical approach in vivo approach
HPLC column
Pharmaceutical equivalence In vivo equivalence
injection
injection
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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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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
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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 = Emax Dose
ED50 + Dose
Hybrid drug and formulation properties (Potency)
Drug property (efficacy)
Effect
Emax
ED50Dose
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ED50 =
Basic assumption to bioequivalence
Clearance EC50
Bioavailability
Drug property
Formulation property
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• Similar plasma concentration profile
same effect?
Basic assumption to bioequivalence
Effect = Emax Dose
Clearance EC50 + Dose
F%
substance properties
Formulation properties
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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
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A4- Ne pas confondre essai de bioéquivalence
et un essai de biodisponibilité
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- 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)
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- 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"
Bioequivalence vs. Bioavailability (II)
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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)
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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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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
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PK/PD relationship to discuss bioequivalence acceptance criteria
Exposure∆ = 20%
Eff
ect
Drug with a narrow margin of safetyDose 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
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Systemic exposureAUC
Does essentially the same plasma time curve leads to essentially the
same effect whether toxic or therapeutic???
±20%
identical
±20%
very different
±40%
Effects
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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 mT/mR 1.25
– log scale log (0.8) µT - µR log 1.25
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Average bioequivalence
reference
test
Same mean
AUC/ Cmax
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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)
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Average bioequivalence
• Addresses only mean (center of distribution) but not variability (shape of distribution)
• Does not address switchability
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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
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Population bioequivalenceAUC 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
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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 and clinicians have titrated the dose to reach a particular goal
• issue for drug of critical therapeutic categories, for elderly, debilitated patients etc.
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Individual bioequivalence
patient-by-formulation interaction
NO
YES
Address switchability“Test” and “reference” are bioequivalent if the individual subject means and variabilities are sufficiently similar with regard to AUC
and Cmax
test
reference
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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)
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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
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Switchability between generics
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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.
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Generic 1
Pioneer
?
yes yes
yes
Generic 2
Generic 3
?
Other reference medicinal product???
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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)
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B-The Bioequivalence trial
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B1-Types of Bioequivalence trials
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Metabolite
Drug C (t)
Drugin
urine
PD1
PD2
.....
Clinicalefficacy
Dose
PK PD Clinical
in vivo testingin vitro testing
Dissolution
abs
Types of bioequivalence trial
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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.
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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
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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
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Pourquoi ne pas utiliser des effets ou des essais cliniques plutôt que des concentrations plasmatiques pour démontrer
une BE?
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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.
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Response A
100 %
50 %
Systemic exposure
ReferenceTest
AUC
T and R are not bioequivalent
Types of Bioequivalence trialPharmacodynamic endpoints
Effe
ct
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Response B
100 %
50 %
Systemic exposure
ReferenceTest
T and R are bioequivalent
AUC
Types of Bioequivalence trialPharmacodynamic endpoints
Effe
ct
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Response A(e.g;of clinical interest)
100 %
50 %
Systemic exposure
ReferenceTest
T and R are bioequivalent
AUC
T and R are not bioequivalent
Types of Bioequivalence trialPharmacodynamic endpoints
Effe
ct Response B(e.g: a surrogate)
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Pharmacological trial
Systemically acting drug
No blood concentration- yes
Blood concentration for highly variable drug- very debatable
Locally acting drug inhalation drug, dermatological preparation etc.- yes
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Generally, poor metrological performance
Type of Bioequivalence trial : clinical trial
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In-vitro dissolution tests
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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
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- 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
in vitro equivalence
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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
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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.
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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
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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
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B2-Bioequivalence trial :
test subjects
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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.)
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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.
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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?
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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)
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Sex, bioavailability and bioequivalence
Sex effectFrequent in human medicine because BW is not considered !
A sex effectAUC
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Sex, bioavailability and bioequivalence
Sex effectFrequent in human medicine because BW 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
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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
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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
–Bioequivalenceno : 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
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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
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– 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
Reasons to exclude females (women) from a BE Trial
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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
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B3- Dose à tester
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Dose to be tested
• The approved dose must be tested
• For drugs with multiple claims
involving different doses, different trials
should be performed
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Single dose vs. multiple doses
steady state studies
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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.
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•Two bio-inequivalent formulations (single
dose) may become bioequivalent in steady-
state condition
Single dose vs. multiple dosesteady state studies
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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
FFormulation2ormulation2
Formulation2
0.0
0.5
1.0
1.5
2.0
2.5
0 50 100 150 200 250 300Time (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
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Multiple-dose studies
• Monte-Carlo simulation (FDA)–the probability of failing the BE test
dramatically decrease upon multiple-dose administration
–multiple dose studies generally not recommended by FDA
– it is possible to conclude to BE for a single dose administration whereas the 2 products are not BE!
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B4-Bioequivalence :Experimental design
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Bioequivalence:experimental design
• Parallel design
• Cross-over design
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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
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- Advantage • no washout period (appropriate for long - acting drug )
• possible unequal numbers of animals per treatment
group
• statistical analysis is still possible when animals are lost
during the experiment
- Limits
• more subjets are required
Bioequivalence : Parallel design
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- 2x2 crossover
- other crossover
e.g. : AB, BA, AA, BB ( BALAAM design )
Bioequivalence : experimental design
1 21
2 A
BA
B
groupsor
sequences
periods
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Bioequivalence : 2x2 crossover design (I)
• Advantage• decrease in the residual error, therefore
reduction in the number of animals
• Limits• washout period required
• risk of an unequal carryover effect
• difficulties in analyzing the design if
animals are lost during the experiment
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B5-Bioequivalence :The a priori
Bioequivalence range
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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
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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.
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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.
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Intervalle de confiance vs. Intervalle de tolérance
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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
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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.
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A priori Bioequivalence range (4)
• For drug with a narrow therapeutic index
0.90 - 1.10 (additive model)0.90 - 1.11 (multiplicative model)
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B6-Bioequivalence sample size
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Bioequivalence : sample size (I)
• The number of subjets 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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Bioequivalence : sample size :multiplicative model
T / R
0.90 1.0 1.10
123880
CV %
exp (2) - 1
102030
6.01632
103268
= 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%
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B8-Bioequivalence :
Characteristics to be investigated
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- AUC, Cmax, Tmax
- Others
- How to calculate or obtain these relevant parameters • Curve fitting vs trapezoidal rule • Cmax, Tmax : observed vs calculated
BE Characteristics to be investigated
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B9-Bioequivalence :
Analytical techniques
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Statistical analysis
• The test problem
• Data analysis - Distribution - Outliers - Logarithmic transformation - 2 x 2 crossover / the carryover effect - Parametric vs. non-parametric
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The test problem
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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
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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
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Classical statistical hypothesis: drawback
F% Ref Testn=1000 n=1000
100
702
Statistically different for p 0.05 but actually therapeutically equivalent
652
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Classical statistical problem : the drawback
F% Ref Testn=3 n=3100
70
30
0Not statistically different for p 0.05 but actually not therapeutically equivalent
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Bioequivalence: the test problem
• The appropriate hypothesis
H01(Ref -test)
H02(Ref -test)
Observation
H0
H1(Ref -test)
1 2
21 inequivalent
equivalent
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Bioequivalence: the test problem
• The appropriate hypothesis
(Ref -test)1 2
H01 H02
two unilateral "t" tests
Can we reject H01? Can we also reject H02?
YES BioequivalentYES
5% 5%
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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
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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
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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 animals : df associated with s
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only the 90 % CI
(administrative bioinequivalence)
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 view 1 A priori B.E. Range 2
Decision procedures in bioequivalence trials
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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 toavoid the use of XR to estimate µR to express 1 and 2
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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 designThe 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 designThe 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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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
• 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
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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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A priori Bioequivalence range
• Pharmacodynamic trial
• ± 20 % or less ?• Surrogates vs. ultimate endpoint
• Clinical trial
± 20 % is unacceptable
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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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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
Pour en savoir plus sur la formulation des hypothèses pour un essai de BE
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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 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)
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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