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NATIONAL VETERINARY SCHOOL TOULOUSE Bioéquivalence & génériques: Science et Polémiques PL Toutain Ecole Nationale Vétérinaire de Toulouse, France Version du 3 février 2009 Toulouse fac med 2009 -1 [PHENYTOIN] µg/mL Change in phenytoin excipients results in epidemic toxicity WEEKS * Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70 Toulouse fac med 2009 - 2 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 Toulouse fac med 2009 -3 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) Toulouse fac med 2009 -4 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 Toulouse fac med 2009 -5 Les génériques Toulouse fac med 2009 -6 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. Toulouse fac med 2009 -7 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 Toulouse fac med 2009 - 8 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 Toulouse fac med 2009 -9 Evolution du marché des génériques en France • Toulouse fac med 2009 - 10 Parts de marché des génériques aux US Proportion des dépenses (%) Proportion des prescriptions (%) Toulouse fac med 2009 - 11 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) Toulouse fac med 2009 - 12 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. Toulouse fac med 2009 - 13 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 Toulouse fac med 2009 - 14 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 Toulouse fac med 2009 - 15 In: Clinical infectious deseases 2005 41 114-117 Toulouse fac med 2009 - 16 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 Toulouse fac med 2009 - 17 Generic competition for drugs availability: Is it a good medicinal practice to encourage the use of old antibiotics rather new ones? Toulouse fac med 2009 - 18 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. Toulouse fac med 2009 - 19 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. Toulouse fac med 2009 - 20 La montée des critiques adressées aux génériques • Publications dans la littérature scientifique – – – – – Anti-épileptiques Cyclosporine Psychotropes Antibiotiques ……. • Opinion des prescripteurs (le testimonial) Toulouse fac med 2009 - 21 Toulouse fac med 2009 - 22 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. Toulouse fac med 2009 - 23 Toulouse fac med 2009 - 24 Le cas des anti-épileptiques Toulouse fac med 2009 - 25 Le cas des anti-épileptiques: remise en cause de la substitution Toulouse fac med 2009 - 26 Le cas des anti-épileptiques : la réponse de l’AFSSAPS Rem: le principe de précaution n’a pas été invoqué pour cette question Toulouse fac med 2009 - 27 La communication de l’assurance maladie Toulouse fac med 2009 - 28 Le médicament générique est la copie exacte du médicament de marque (Site Web de l’assurance maladie) La communication de l’AM est militante Toulouse fac med 2009 - 29 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. Toulouse fac med 2009 - 30 The case of antiepileptic drugs Toulouse fac med 2009 - 31 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. Toulouse fac med 2009 - 32 France-Soir du 24 janvier 2009 Toulouse fac med 2009 - 33 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 ? Toulouse fac med 2009 - 34 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. Toulouse fac med 2009 - 35 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 Toulouse fac med 2009 - 36 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 Toulouse fac med 2009 - 37 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 Toulouse fac med 2009 - 38 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. Toulouse fac med 2009 - 39 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. Toulouse fac med 2009 - 40 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. Toulouse fac med 2009 - 41 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!! Toulouse fac med 2009 - 42 Le blog d'Eric Gibert - DocCheck Blog Toulouse fac med 2009 - 43 A-Bioéquivalence: considérations techniques et scientifiques Toulouse fac med 2009 - 44 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. Toulouse fac med 2009 - 45 A1-Bioequivalence : Definition and assumptions Toulouse fac med 2009 - 46 Bioequivalence : Definition 2009 (I) • 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 •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 Toulouse fac med 2009 - 47 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. Toulouse fac med 2009 - 48 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 Toulouse fac med 2009 - 49 A2-Pourquoi le plasma pour démontrer la bioéquivalence? Toulouse fac med 2009 - 50 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 ! Toulouse fac med 2009 - 51 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 ? Toulouse fac med 2009 - 52 A3-Pourquoi utiliser le concept de biodisponibilité pour démontrer une bioéquivalence Toulouse fac med 2009 - 53 Basic assumption to bioequivalence Similar plasma concentration profile same effect ? Why ? Effect Drug property (efficacy) Effect = Emax Emax Dose ED50 + Dose ED50 Dose Hybrid drug and formulation properties (Potency) Toulouse fac med 2009 - 54 Basic assumption to bioequivalence Drug property ED50 = Clearance EC50 Bioavailability Formulation property Toulouse fac med 2009 - 55 Basic assumption to bioequivalence • Similar plasma concentration profile same effect? Effect = substance properties Emax Dose Clearance EC50 + Dose F% Formulation properties Toulouse fac med 2009 - 56 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 Toulouse fac med 2009 - 57 A4- Ne pas confondre essai de bioéquivalence et un essai de biodisponibilité Toulouse fac med 2009 - 58 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 • ••••• Toulouse fac med 2009 - 59 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" Toulouse fac med 2009 - 60 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 Toulouse fac med 2009 - 61 A5-Does essentially the same plasma time curve leads to essentially the same effect whether toxic or therapeutic? Toulouse fac med 2009 - 62 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 Toulouse fac med 2009 - 63 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 Toulouse fac med 2009 - 64 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% Toulouse fac med 2009 - 65 A6-Les différents définitions statistiques possibles d’ une bioéquivalence Toulouse fac med 2009 - 66 Average vs. population bioequivalence vs. individual bioequivalence Toulouse fac med 2009 - 67 Different types of bioequivalence • Average (ABE) : mean • Population (PBE) : prescriptability • Individual (IBE) : switchability Toulouse fac med 2009 - 68 FDA: Guidance Update: Average, Population, and Individual Approaches to Establishing Bioequivalence Toulouse fac med 2009 - 69 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 Toulouse fac med 2009 - 70 Average bioequivalence reference test AUC/ Cmax Same mean Toulouse fac med 2009 - 71 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) Toulouse fac med 2009 - 72 Average bioequivalence • Addresses only mean (center of distribution) but not variability (shape of distribution) • Does not address switchability Toulouse fac med 2009 - 73 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 Toulouse fac med 2009 - 74 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 Toulouse fac med 2009 - 75 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. Toulouse fac med 2009 - 76 Individual bioequivalence test patient-by-formulation interaction NO reference YES Address switchability “Test” and “reference” are bioequivalent if the individual subject means and variabilities are sufficiently similar with regard to AUC and Cmax Toulouse fac med 2009 - 77 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) Toulouse fac med 2009 - 78 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 Toulouse fac med 2009 - 79 Switchability between generics Toulouse fac med 2009 - 80 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. Toulouse fac med 2009 - 81 ? Generic 2 Generic 1 yes yes ? yes Pioneer ??? Generic 3 Other reference medicinal product Toulouse fac med 2009 - 82 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) Toulouse fac med 2009 - 83 B-The Bioequivalence trial Toulouse fac med 2009 - 84 B1-Types of Bioequivalence trials Toulouse fac med 2009 - 85 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 Toulouse fac med 2009 - 86 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. Toulouse fac med 2009 - 87 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 Toulouse fac med 2009 - 88 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 - 89 Toulouse fac med 2009 Pourquoi ne pas utiliser des effets ou des essais cliniques plutôt que des concentrations plasmatiques pour démontrer une BE? Toulouse fac med 2009 - 90 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. Toulouse fac med 2009 - 91 Types of Bioequivalence trial Pharmacodynamic endpoints Test Reference Effect 100 % Response A 50 % T and R are not bioequivalent Systemic exposure AUC Toulouse fac med 2009 - 92 Types of Bioequivalence trial Pharmacodynamic endpoints Test Reference Effect 100 % Response B 50 % T and R are bioequivalent Systemic exposure AUC Toulouse fac med 2009 - 93 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 Toulouse fac med 2009 - 94 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. Toulouse fac med 2009 - 95 - yes Type of Bioequivalence trial : clinical trial Generally, poor metrological performance Toulouse fac med 2009 - 96 In-vitro dissolution tests Toulouse fac med 2009 - 97 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 Toulouse fac med 2009 - 98 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 Toulouse fac med 2009 - 99 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 Toulouse fac med 2009 - 100 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. Toulouse fac med 2009 - 101 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 Toulouse fac med 2009 - 102 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 Toulouse fac med 2009 - 103 B2-Bioequivalence trial : test subjects Toulouse fac med 2009 - 104 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.) Toulouse fac med 2009 - 105 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. Toulouse fac med 2009 - 106 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? Toulouse fac med 2009 - 107 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) Toulouse fac med 2009 - 108 Sex, bioavailability and bioequivalence A sex effect AUC Sex effect Frequent in human medicine because BW is not considered ! Toulouse fac med 2009 - 109 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 BW is not considered ! Toulouse fac med 2009 - 110 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) * Toulouse fac med 2009 - 111 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 Toulouse fac med 2009 - 112 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 Toulouse fac med 2009 - 113 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 Toulouse fac med 2009 - 115 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 Toulouse fac med 2009 - 116 B3- Dose à tester Toulouse fac med 2009 - 117 Dose to be tested • The approved dose must be tested • For drugs with multiple claims involving different doses, different trials should be performed Toulouse fac med 2009 - 118 Single dose vs. multiple doses steady state studies Toulouse fac med 2009 - 120 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. Toulouse fac med 2009 - 121 Single dose vs. multiple dose steady state studies •Two bio-inequivalent formulations (single dose) may become bioequivalent in steadystate condition Toulouse fac med 2009 - 122 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 Toulouse fac med 2009 - 123 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 single dose administration whereas the 2 products are not BE! Toulouse fac med 2009 - 125 B4-Bioequivalence : Experimental design Toulouse fac med 2009 - 126 Bioequivalence: experimental design • Parallel design • Cross-over design Toulouse fac med 2009 - 127 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) Toulouse fac med 2009 - 128 Bioequivalence : Parallel design - 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 Toulouse fac med 2009 - 129 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 ) Toulouse fac med 2009 - 131 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 Toulouse fac med 2009 - 132 B5-Bioequivalence : The a priori Bioequivalence range Toulouse fac med 2009 - 133 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 Toulouse fac med 2009 - 134 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. Toulouse fac med 2009 - 135 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 ToulouseBE. fac med 2009 - 136 formulations qui seraient réellement différentes de 15-20% puissent être déclarées Intervalle de confiance vs. Intervalle de tolérance Toulouse fac med 2009 - 137 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 Toulouse fac med 2009 - 138 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. Toulouse fac med 2009 - 139 A priori Bioequivalence range (4) • For drug with a narrow therapeutic index 0.90 - 1.10 (additive model) 0.90 - 1.11 (multiplicative model) Toulouse fac med 2009 - 140 B6-Bioequivalence sample size Toulouse fac med 2009 - 141 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 Toulouse fac med 2009 - 142 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 Toulouse fac med 2009 - 143 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% Toulouse fac med 2009 - 144 B8-Bioequivalence : Characteristics to be investigated Toulouse fac med 2009 - 145 BE Characteristics to be investigated - AUC, Cmax, Tmax - Others - How to calculate or obtain these relevant parameters • Curve fitting vs trapezoidal rule • Cmax, Tmax : observed vs calculated Toulouse fac med 2009 - 146 B9-Bioequivalence : Analytical techniques Toulouse fac med 2009 - 147 Statistical analysis • The test problem • Data analysis - Distribution - Outliers - Logarithmic transformation - 2 x 2 crossover / the carryover effect - Parametric vs. non-parametric Toulouse fac med 2009 - 149 The test problem Toulouse fac med 2009 - 150 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 Toulouse fac med 2009 - 151 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 Toulouse fac med 2009 - 152 Classical statistical hypothesis: drawback F% Ref n=1000 Test n=1000 100 702 652 Statistically different for p 0.05 but actually therapeutically equivalent Toulouse fac med 2009 - 153 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 Toulouse fac med 2009 - 154 Bioequivalence: the test problem • The appropriate hypothesis H02 (Ref -test) H01 (Ref -test) H0 q1 inequivalent q2 equivalent (Ref -test) H1 Observation q2 q1 Toulouse fac med 2009 - 155 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 Toulouse fac med 2009 - 156 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 Toulouse fac med 2009 - 157 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 Toulouse fac med 2009 - 158 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 - 159 Toulouse fac med 2009 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 Toulouse fac med 2009 - 160 Pharmacometric aspects Toulouse fac med 2009 - 161 Statistical analysis (EMEA 2009) • The data should be transformed prior to analysis using a logarithmic transformation. Toulouse fac med 2009 - 162 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 t avoid the use of XR to estimate µR to express and 2 Toulouse fac med 2009 - 164 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 Toulouse fac med 2009 - 166 The 2x2 cross-over design The period effect • Not desirable • Does not invalidate a cross-over design • Origin : enzymatic induction, environment, equal carryover Toulouse fac med 2009 - 167 The 2x2 cross-over design The formulation effect • Possible • Does not invalidate the BE conclusions Toulouse fac med 2009 - 168 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 Toulouse fac med 2009 - 169 The 2x2 cross-over design the carryover effect Toulouse fac med 2009 - 170 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") Toulouse fac med 2009 - 171 The carryover effect If the carryover effects are unequal, no unbiased estimate exists for the direct effects from both periods Toulouse fac med 2009 - 172 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 Toulouse fac med 2009 - 173 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 Toulouse fac med 2009 - 174 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. Toulouse fac med 2009 - 175 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. Toulouse fac med 2009 - 176 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 . Toulouse fac med 2009 - 177 A priori Bioequivalence range for drug with a narrow therapeutic index 0.90 - 1.10 (Untransformed) 0.90 - 1.11 (Ln-transformed) Toulouse fac med 2009 - 178 A priori Bioequivalence range • Pharmacodynamic trial • ± 20 % or less ? • Surrogates vs. ultimate endpoint • Clinical trial ± 20 % is unacceptable Toulouse fac med 2009 - 179 Bioequivalence sample size Toulouse fac med 2009 - 180 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 Toulouse fac med 2009 - 181 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 Toulouse fac med 2009 - 182 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 Pour en savoir plus sur la formulation des hypothèses pour un essai de BE Toulouse fac med 2009 - 183 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) Toulouse fac med 2009 - 184 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% Toulouse fac med 2009 - 185 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 Toulouse fac med 2009 - 186