Bioéquivalence & génériques: S cience et Polémiques

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


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


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

http://www.emea.europa.eu/pdfs/human/qwp/140198enrev1.pdf

http://www.emea.europa.eu/pdfs/human/qwp/140198enrev1.pdf

http://www.emea.eu.int/pdfs/human/ewp/4032606en.pdf




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)


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

http://www.fda.gov/cder/Guidance/3616fnl.pdf









Les génériques


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.


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


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


Evolution du marché des génériques en France

•


Parts de marché des génériques aux US

Proportion des dépenses (%) Proportion des prescriptions (%)


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)


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.


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


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


In: Clinical infectious deseases 2005 41 114-117


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


Generic competition for drugs availability:

Is it a good medicinal practice to encourage the use of old

antibiotics rather new ones?


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.


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.


La montée des critiques adressées aux génériques

• Publications dans la littérature scientifique– Anti-épileptiques– Cyclosporine– Psychotropes– Antibiotiques– …….

• Opinion des prescripteurs (le testimonial)



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.



Le cas des anti-épileptiques

http://www.imagence.com/UserFiles/IGWSImagence/File/pdf/CommuniqueLFCE.pdf


Le cas des anti-épileptiques:remise en cause de la substitution


Rem: le principe de précaution n’a pas été

invoqué pour cette question

Le cas des anti-épileptiques :la réponse de l’AFSSAPS


La communication de l’assurance maladie


Le médicament générique est la copie exacte du médicament de marque(Site Web de l’assurance maladie)

La communication de l’AM est militante


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.

http://fr.wikipedia.org/wiki/Acide_valpro%C3%AFque

http://fr.wikipedia.org/wiki/Acide_valpro%C3%AFque

http://fr.wikipedia.org/wiki/Lamotrigine


The case of antiepileptic drugs


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.

http://fr.wikipedia.org/wiki/AFSSAPS


France-Soir du 24 janvier 2009


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 ?


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.

http://jama.ama-assn.org/cgi/content/short/301/3/252


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


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


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



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.



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.



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.


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!!


Le blog d'Eric Gibert - DocCheck Blog

http://blog.doccheck.com/fr/blogs/16




A-Bioéquivalence: considérations techniques et

scientifiques


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.


A1-Bioequivalence :Definition and assumptions


• 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


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.


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


A2-Pourquoi le plasma pour démontrer la bioéquivalence?


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 !


Is there an univocal relationship between exposure and effect ?

Basic assumption to bioequivalence

Yes/No ?

yes

yes

Effectsnot driven by plasma

concentrations

Plasma concentrations

DOSE Effectsdriven by plasma concentrations

Yes

Plasma concentrations

yesYes


A3-Pourquoi utiliser le concept de biodisponibilité

pour démontrer une bioéquivalence



Similar plasma concentration profile same effect ?

Why ?

Effect = Emax Dose

ED50 + Dose

Hybrid drug and formulation properties (Potency)

Drug property (efficacy)

Effect

Emax

ED50Dose

Didier CONCORDET

modèle trop particulierApproximation de la division


ED50 =


Clearance EC50

Bioavailability

Drug property

Formulation property


• Similar plasma concentration profile

same effect?


Effect = Emax Dose

Clearance EC50 + Dose

F%

substance properties

Formulation properties



• Similar plasma concentration same effect? • Comparison of 2 formulations of the same drug

Effect, pioneer = Emax Dose

Clearance EC50

F,ref

Effect,test = Emax Dose

Clearance EC50

F,test

Vs.

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

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

+ Dose + Dose


A4- Ne pas confondre essai de bioéquivalence

et un essai de biodisponibilité


- Bioavailability trials must document

influence of different factors on the rate

and extent of drug absorption

• age

• sex

• route of administration

• disease

• •••••

Bioequivalence vs. Bioavailability (I)


- 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)


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)


A5-Does essentially the same plasma time curve leads to

essentially the same effect whether toxic or

therapeutic?


PK/PD relationship to discuss bioequivalence acceptance criteria

Exposure∆ = 20%

Eff

ect

Drug with a large margin of safety

Dose may be selected in the asymptotic part of the dose-effect relationship

curve and a Δ of 20% for exposure is generally

irrelevant in terms of effect


PK/PD relationship to discuss bioequivalence acceptance criteria

Exposure∆ = 20%

Eff

ect

Drug with a narrow margin of 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


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


A6-Les différents définitions statistiques possibles d’ une

bioéquivalence


Average vs.

population bioequivalence vs.

individual bioequivalence


Different types of bioequivalence

• Average (ABE) : mean

• Population (PBE) : prescriptability

• Individual (IBE) : switchability


FDA: Guidance Update: Average, Population, and Individual Approaches to Establishing Bioequivalence

http://www.fda.gov/ohrms/dockets/ac/00/slides/3657s2_03/index.htm






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



reference

test

Same mean

AUC/ Cmax



Average B.E. refers to the location parameters

Average B.E. may not be sufficient to guarantee that an individual patient could be switched from a reference to a generic formulation

(e.g., more than 50 % of subjects may be outside the B.E. range when the average B.E. is actually demonstrated)



• Addresses only mean (center of distribution) but not variability (shape of distribution)

• Does not address switchability


Prescribability

• Refer to the clinical setting in which a practitioner prescribes a drug product to a patient for the first time

• he has no information on his patient• the prescriber needs to know the

comparability of the 2 or n formulations in the population

population bioequivalence


Population 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


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.


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


Individual bioequivalence

• The clinical relevance of a subject-by-formulation interaction has not clearly been demonstrated–e.g.: a pH-specific excipient effect

associated with certain diazepam formulations result in producing unequivalence when administered to individuals with elevated gastric pH (like elderly)


The types of bioequivalence: summary

Average Population Individual

Pioneer

Test

Only guarantees on the mean

Guarantees an overall distribution (mean and variance)

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


Switchability between generics


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.


Generic 1

Pioneer

?

yes yes

yes

Generic 2

Generic 3

?

Other reference medicinal product???


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)


B-The Bioequivalence trial


B1-Types of Bioequivalence trials


Metabolite

Drug C (t)

Drugin

urine

PD1

PD2

.....

Clinicalefficacy

Dose

PK PD Clinical

in vivo testingin vitro testing

Dissolution

abs

Types of bioequivalence trial


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.


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


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


Pourquoi ne pas utiliser des effets ou des essais cliniques plutôt que des concentrations plasmatiques pour démontrer

une BE?


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.


Response A

100 %

50 %

Systemic exposure

ReferenceTest

AUC

T and R are not bioequivalent

Types of Bioequivalence trialPharmacodynamic endpoints

Effe

ct


Response B

100 %

50 %

Systemic exposure

ReferenceTest

T and R are bioequivalent

AUC


Effe

ct


Response A(e.g;of clinical interest)

100 %

50 %

Systemic exposure

ReferenceTest

T and R are bioequivalent

AUC

T and R are not bioequivalent


Effe

ct Response B(e.g: a surrogate)


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


Generally, poor metrological performance

Type of Bioequivalence trial : clinical trial


In-vitro dissolution tests


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


- 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


In vitro testing (EMEA 2009)

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


In-vitro 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.


In vitro testing: data analysis

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

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


The Bioequivalence trial

• Selection of subjects

• Reference material

• Dose to be tested (single vs. multiple)

• Administration / Sampling

• Design

• The a priori Bioequivalence range

• The sample size

• Characteristics to be investigated


B2-Bioequivalence trial :

test subjects


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.)


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.


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?


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)


Sex, bioavailability and bioequivalence

Sex effectFrequent in human medicine because BW is not considered !

A sex effectAUC



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



Interaction sex * formulation

(A vs. B)

A B

A

B

BE

not BE

Les 2 formulations sont BE chez la femme mais pas chez l’homme; il y a donc une interaction sexe*formulation



• Question: do we need to test both sexes?–Bioavailability

yes : possible sex effect frequent in human medicine because BW is not taken into account for dosage regimen

–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


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


– 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


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


B3- Dose à tester


Dose to be tested

• The approved dose must be tested

• For drugs with multiple claims

involving different doses, different trials

should be performed


Single dose vs. multiple doses

steady state studies


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.


•Two bio-inequivalent formulations (single

dose) may become bioequivalent in steady-

state condition

Single dose vs. multiple dosesteady state studies


0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 50 100 150 200 250 300

Time (h)

1

2

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

Formulation1

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


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!


B4-Bioequivalence :Experimental design


Bioequivalence:experimental design

• Parallel design

• Cross-over design


Parallel design

subjects

Group 1Formulation 1

Group 2 Formulation 2

Randomly assigned to treatments

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

Groups and formulations are confounded


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

• possible unequal numbers of animals per treatment

group

• statistical analysis is still possible when animals are lost

during the experiment

- Limits

• more subjets are required

Bioequivalence : Parallel design


- 2x2 crossover

- other crossover

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

Bioequivalence : experimental design

1 21

2 A

BA

B

groupsor

sequences

periods


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


B5-Bioequivalence :The a priori

Bioequivalence range


A priori Bioequivalence range

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

which the 90 % CI interval of the ratio of

the two product should be located in order

to accept average B.E.

•To be defined by the clinician


Acceptance limits (EMEA 2009)

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

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

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


the 90 % CI of the ratio

BE accepted

1 2

Decision procedures in bioequivalence trials

80%+125%

µT / µRRatio of test and reference formulation

BE not accepted

BE not accepted

C’est l’Intervalle de confiance du rapport des AUC qui doit être entre les bornes et non le rapport lui même et sauf à prendre un nombre de sujets très grand, on ne peut pas imaginer que 2

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


Intervalle de confiance vs. Intervalle de tolérance


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


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.


A priori Bioequivalence range (4)

• For drug with a narrow therapeutic index

0.90 - 1.10 (additive model)0.90 - 1.11 (multiplicative model)


B6-Bioequivalence sample size


Bioequivalence : sample size (I)

• The number of 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


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

: The bioequivalence range ( ± 20 % )

: The consumer risk (5 % )

: The producer risk (e.g., 20 % )( the probability of rejecting bioequivalence when products are actually bioequivalent. Power is used only in planning the experiment, not as part of the statistical test )

: The error / (residual) variance


Bioequivalence : sample size :multiplicative model

T / R

0.90 1.0 1.10

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%


B8-Bioequivalence :

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

BE Characteristics to be investigated


B9-Bioequivalence :

Analytical techniques


Statistical analysis

• The test problem

• Data analysis - Distribution - Outliers - Logarithmic transformation - 2 x 2 crossover / the carryover effect - Parametric vs. non-parametric


The test problem


Bioequivalence : the test problem

From a regulatory point of view the producer risk of erroneously rejecting bioequivalence is of no importance

The primary concern is the protection of the patient (consumer risk) against the acceptance of BE if it does not hold true


H 0 : T - R =

Bioequivalence : the test problem

Classical test of null hypothesis (I)

H 1 : T - R

T and R : population mean for test and

reference formulation respectively

Decision on the BE cannot be based on the classical null hypothesis

or T = R

or T R


Classical statistical hypothesis: drawback

F% Ref Testn=1000 n=1000

100

702

Statistically different for p 0.05 but actually therapeutically equivalent

652


Classical statistical problem : the drawback

F% Ref Testn=3 n=3100

70

30

0Not statistically different for p 0.05 but actually not therapeutically equivalent


Bioequivalence: the test problem

• The appropriate hypothesis

H01(Ref -test)

H02(Ref -test)

Observation

H0

H1(Ref -test)

1 2

21 inequivalent

equivalent


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%


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



Use of the classical null hypothesis would

encourage poor trials, with few subjects,

under uncontrolled conditions to answer

an irrelevant question


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


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


Pharmacometric aspects


Statistical analysis (EMEA 2009)

• The data should be transformed prior to analysis using a logarithmic transformation.


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


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


The 2x2 cross-over designThe period effect

• Not desirable

• Does not invalidate a cross-over design

• Origin : enzymatic induction, environment, equal carryover


The 2x2 cross-over designThe formulation effect

• Possible

• Does not invalidate the BE conclusions


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


The 2x2 cross-over design

the carryover effect


The carryover effect

• The direct drug effect is the effect that

a drug produces during the period in

which the drug is administered

• The carryover effect is the drug effect

that persists after the end of the dosing

period ("memory effect")



If the carryover effects are unequal,

no unbiased estimate exists for the

direct effects from both periods



• The washout period is the rest period between 2 treatment periods

• The duration depends on the drug

• Should be long enough to avoid a carryover effect

Origin: a too short washout period


Equal vs. unequal cary-over effect

Period 1 Period 2

A B

B A

Period 1 Period 2

A B

B A

Equal carryover effect give a period

effect

Unequal carry-over effect give a sequence effect that is totally confounded in a 2x2

crossover design with a formulation-by-period

interaction


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.


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.


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 .


A priori Bioequivalence range for drug with a narrow therapeutic index

0.90 - 1.10 (Untransformed)0.90 - 1.11 (Ln-transformed)


A priori Bioequivalence range

• Pharmacodynamic trial

• ± 20 % or less ?• Surrogates vs. ultimate endpoint

• Clinical trial

± 20 % is unacceptable


Bioequivalence sample size


Bioequivalence : sample size (I)

• The number of subjects has not to be

justified if the appropriate risk is

controlled (consumer risk, 5 %)

• For economical and ethical reasons, the

appropriate number of subjects must be

calculated to avoid an excessively high

producer risk


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

: The bioequivalence range ( ± 20 % )

: The consumer risk (5 % )

: The producer risk (e.g., 20 % )( the probability of rejecting bioequivalence when products are actually bioequivalent. Power is used only in planning the experiment, not as part of the statistical test )

: The error / (residual) variance



• 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

http://physiologie.envt.fr/spip/spip.php?article81

http://physiologie.envt.fr/spip/spip.php?article81


Conclusions (1)

1.Personne ne conteste globalement l’intérêt des génériques

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

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

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

• gestion du risque (le droit de substitution)• communication sur le risque (et non de la propagande)


Conclusions (2)

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

• L’approche pharmacocinétique plutôt que pharmacodynamique et clinique

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

• La dose unique plutôt que des doses multiples• Le nombre de sujets, même faible, si le risque statistique

approprié (celui du patient) est contrôlé• Sont discutables et méritent d’être discuté:

• La non démonstration statistique de la « substituabilité » (switchability) des formulations (princeps vs. génériques et génériques entre eux)

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

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


Conclusions (3)

2-Aspects de gestion du risque• Est discutable et mérite d’être discutée la politique

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

étroites (anti-épileptiques, anti-arythmiques….,) ou encore pour les populations à risque, le prescripteur devrait être le décideur par défaut

3-Les aspects industriels/BPF• Les contrôles dans certains pays (Chine, Inde,

Brésil..)

4-Tout ce qui tourne autour de l’observance

Documents

Bioéquivalence & génériques: S cience et Polémiques