A-Bioéquivalence: considérations techniques et scientifiques

A-Bioéquivalence: considérations techniques et scientifiques

Une revue technique récente en français

A1-Bioequivalence : Definition and assumptions

Principe de l’essai de bioéquivalence
? = Approche analytiqque Equivalence pharmaceutique: % au moins 24 mois Levothyrox: ancienne formulation: % pour 36 mois

Principe de l’essai de bioéquivalence
? = Approche in vivo Concentrations plasmatiques Concentrations plasmatiques Bioéquivalence: ≤80-125% avec un risque <5%:

Pourquoi des preuves pharmacocinétique (mesure des concentrations plasmatiques) pour démontrer la bioéquivalence plutôt qu’un essai clinique ou la mesure d’effets?

Essais cliniques Coût prohibitif annulant l’intérêt des génériques
Coût> plusieurs 100M€ Générique: beaucoup moins cher mais 32M€ pour le lévothyrox Impossibilité statistique de démontrer une équivalence On sait démontrer une non-infériorité mais pas une équivalence avec un intervalle % avec un risque de 5%

A2-Pourquoi le plasma pour démontrer la bioéquivalence?

Pourquoi des concentrations plasmatiques et pas des effets
L’hypothèse de base est que si les concentrations plasmatiques sont très proches (similaires) alors les tous effets seront essentiellement les mêmes.

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 !

Basic assumption to bioequivalence
Is there an univocal relationship between exposure and effect ? DOSE Effects driven by plasma concentrations yes Plasma concentrations yes Yes yes Yes Effects not driven by plasma concentrations Plasma concentrations Yes/No ?

A3-Pourquoi utiliser le concept de biodisponibilité pour démontrer une bioéquivalence

Similar plasma concentration profile  same effect ? Why ? Effect = Effect Substance property (efficacy) Emax Emax  Dose ED50 + Dose ED50 Dose Hybrid substance and formulation properties (Potency)

Substance property Clearance  EC50 Bioavailability ED50 = Formulation property

Similar plasma concentration profile  same effect? substance properties Emax  Dose Clearance  EC50 + Dose F% Effect = Formulation properties

Similar plasma concentration  same effect? Comparison of 2 formulations of the same drug Emax  Dose Clearance  EC50 F,ref Emax  Dose Clearance  EC50 F,test Effect, pioneer = Vs. Effect,test = + Dose + Dose 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

A4- Ne pas confondre essai de bioéquivalence et un essai de biodisponibilité

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 • •••••

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

Bioequivalence vs. Bioavailability (IV)
Inference from a trial - Bioavailability No generalization from a subgroup of subjects to the population - Bioequivalence If B.E. is demonstrated in a particular subgroup of subjects, conclusion should be extended to whole population unless there is an interaction between formulation and a constitutional factor

Bioequivalence : Factor of variability to control (I)
Species B.E. of two formulations has to be demonstrated in each species (interaction between formulation and species is systematically hypothesized ) Food interactions This factor of variability addresses questions essentially related to the pharmaceutical form and not related to the future patient population

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
Effect 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 Exposure ∆ = 20%

PK/PD relationship to discuss bioequivalence acceptance criteria
Effect 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 Exposure ∆ = 20%

Does essentially the same plasma time curve leads to essentially the same effect whether toxic or therapeutic? Effects identical ±40% very different AUC Systemic exposure ±20% ±20%

Conséquence d’une variation de ± 20 % de l’exposition sur l’amplitude des variations des effets désirés (courbe bleue) et des effets indésirables (courbe brune)

A6-Les différentes définitions statistiques possibles d’ une bioéquivalence

Average vs. population bioequivalence vs. individual bioequivalence

Different types of bioequivalence
Average (ABE) : mean Population (PBE) : prescriptability Individual (IBE) : switchability

Average bioequivalence
reference test AUC/ Cmax Same mean

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 bioequivalence AUC distribution
No Yes “Test” and “reference” are bioequivalent if the entire population distribution (mean and variability) are sufficiently similar with regard to AUC and Cmax

Bioéquivalence moyenne et fenêtre thérapeutique

Switchability Refer to the clinical setting in which a practitioner transfers a patient from one drug product to another We have information on the response of the patient to a particular formulation (princeps or a generic) and clinicians have titrated the dose to reach a particular goal issue for drug of critical therapeutic categories, for elderly, debilitated patients etc.

Individual bioequivalence
patient-by-formulation interaction YES No test reference Address switchability “Test” and “reference” are bioequivalent if the individual subject means and variabilities are sufficiently similar with regard to AUC and Cmax; Ce concept est pratiquement abandonné car trop difficile à mettre en évidence

Individual bioequivalence
The clinical relevance of a subject-by-formulation interaction has not clearly been demonstrated e.g.: a pH-specific excipient effect associated with certain diazepam formulations result in producing unequivalence when administered to individuals with elevated gastric pH (like elderly)

The types of bioequivalence: summary
Average Population Individual Pioneer Test Only guarantees on the mean Guarantees an overall distribution (mean and variance) Test of no interaction between patient and formulation guarantees an individual BE

Substitution entre les génériques

Foisonnement actuel des génériques
503 AMM de générique en 2013

Foisonnement actuel des génériques : les problèmes
Quid de la substitution entre génériques Quid du risque nominal de 5% qui est retenu dans les études de BE Quid de la traçabilité, de la pharmacovigilance (effet de dilution de l’info?) etc.

Guideline on the investigation of bioequivalence (2009)
It is said: Furthermore, this guideline does not cover aspects related to generic substitution as this is subject to national legislation. Ce n’est pas un problème scientifique mais une mesure de gestion

Other reference medicinal product
? Generic 2 Generic 1 yes yes ? yes Generic 3 Pioneer Other reference medicinal product ???

L’intervalle ce confiance du ratio doit être intégralement contenu dans l’intervalle d’équivalence

IC de différents génériques et BE des génériques entre eux

Différences entre génériques: AUC

Différences entre génériques: Cmax

Possibilité théoriques de faire des méta-analyses pour vérifier que les génériques sont BE entre eux mais les résultats seraient ingérables en cas de différence Chow SC, Shao J. Bioequivalence review for drug interchangeability. J Biopharm Stat 1999;9(3):

B-The Bioequivalence trial

B1-Types of Bioequivalence trials

Types of bioequivalence trials
Metabolite PD1 Dose abs Drug C (t) PD2 Clinical efficacy Dissolution ..... Drug in urine PK PD Clinical in vitro testing in vivo testing

Types of bioequivalence trial in vivo : metabolite plasma profile (I)
When no analytical technique exists for drug but does exist for a primary inactive metabolite The administered drug is a prodrug which is very rapidly transformed to an active metabolite

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

Essais cliniques Coût prohibitif annulant l’intérêt des génériques
Coût> plusieurs 100M€ Générique: beaucoup moins cher mais 32M€ pour le lévothyrox Impossibilité statistique de démontrer une équivalence On sait démontrer une non-infériorité mais pas une équivalence avec un intervalle % avec un risque de 5%

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. Cas des biosimilaires

Types of Bioequivalence trial Pharmacodynamic endpoints
Test Reference 100 % Response A Effect 50 % T and R are not bioequivalent Systemic exposure AUC

Test Reference 100 % Response B Effect 50 % T and R are bioequivalent Systemic exposure AUC

Test Reference 100 % Response B (e.g: a surrogate) Effect Response A (e.g;of clinical interest) 50 % T and R are not bioequivalent T and R are bioequivalent Systemic exposure AUC

Pharmacodynamic endpoint
An essential component of BE study based on a PD response is documentation of a dose-response relationship The BE should be conducted in the sensitive region of dose-response curve A BE study conducted near the plateau of response will be insensitive to differences in drug

Locally acting drug products
Issue: measurable concentrations of drug in an accessible biological fluid may not be produced or the clinical efficacy may not be correlated to systemic levels Solution (FDA): other approaches for assessing BE pharmacodynamic endpoint clinical endpoint in vitro studies

Type of Bioequivalence trial : clinical trial
Generally, poor metrological performance Approche retenue pour les biosimilaires

Exception aux essais in vivo et possibilité de les remplacer par des tests in-vitro de dissolution

Guideline on the investigation of bioequivalence (2009): In vitro equivalence
When the active substance in test and reference products are identical or contain comparable salts, in vivo bioequivalence studies may, in some situations, not be required as described in APPENDIX II (bioequivalence study requirements) and III (biowaiver).

IV solutions (EMEA 2009) Bioequivalence studies are not required if the test product is to be administered as an aqueous intravenous solution containing the same active substance as the currently approved product. Moreover, the excipients, pH and osmolality have to be the same or, at least, comparable and should not interact with the drug substance (e.g. complex formation).

Parenteral solutions (EMEA 2009)
In the case of other parenteral routes, e.g. intramuscular or subcutaneous, and the test product is of the same type of solution (aqueous or oily), contains the same concentration of the same active substance and the same excipients in similar amounts as the medicinal product currently approved, bioequivalence studies are not required.

Oral solutions (EMEA 2009) If the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution, bioequivalence studies may be waived, if the excipients contained in it do not affect gastrointestinal transit, absorption , solubility or in-vivo stability of the active substance.

In vitro testing: interpretation of results (EMEA 2009)
In cases where more than 85% of the drug is dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation, except in the case of gastro-resistant formulations where the dissolution takes place in the intestine and the 15 minutes for gastric-emptying lacks of physiological meaning

In vitro equivalence The disintegration vs. the absorption phase
The logic to support an in vitro testing to waive in vivo study rather than to demonstrate a bioequivalence

In vitro testing (EMEA 2009)
The results of in vitro dissolution tests at least at pH 1.2, 4.5, 6.8 and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported

In vitro testing: data analysis
The similarity may be compared by model- independent or model-dependent methods e.g. by statistical multivariate comparison of the parameters of the Weibull function or the percentage dissolved at different time points, or by calculating a similarity factor e.g. the f2 similarity factor defined below. In this equation ƒ2 is the similarity factor, n is the number of time points, R (t) is the mean percent drug dissolved of e.g. a reference product, and T(t) is the mean percent drug dissolved of e.g. a test product

The Bioequivalence trial
• Selection of subjects • Reference material • Dose to be tested (single vs. multiple) • Administration / Sampling • Design • The a priori Bioequivalence range • The sample size • Characteristics to be investigated

B2-Bioequivalence trial : test subjects

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 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
A sex effect AUC Sex effect Frequent in human medicine because Body Weight is not considered for dosage regimen!

Un effet sexe (ou tout autre effet comme ceux liés à l’âge, l’état de santé…) relatif à un médicament n’est pas un problème pour la démonstration d’une BE ; ce qui poserait problème serait une interaction entre l’un de ces effets et la formulation A B A B BE Sex effect Frequent in human medicine because Body Weight is not considered !

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)

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:

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

Gender representation in trials
US congress enacts legislation to require that a clinical trial must be “designed and carried out in a manner sufficient to provide for a valid analysis of whether the variables being studied in the trial affect women… differently than other subjects in the trial”

Reference material in Bioequivalence (Guideline EMEA 2009)
the chosen reference medicinal product must be a medicinal product authorised in the Community, on the basis of a complete dossier in accordance with the provisions of Article 8 of Directive 2001/83/EC, as amended. The product used as reference product in the bioequivalence study should be part of the global marketing authorisation of the reference medicinal product. The choice of the reference medicinal product should be justified by the applicant.

B3- Dose à tester

Dose to be tested The approved dose must be tested
For drugs with multiple claims involving different doses, different trials should be performed

Single dose vs. multiple doses steady state studies

Single dose vs. multiple dose steady state studies: Guideline on the investigation of BE (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.

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 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 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 50 100 150 200 250 300 Time (h) 1 2 K01=0.1 vs 0.05h-1. Multiple doses administrations Formulation2 Formulation1

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 multiple dose administration whereas the 2 products are not BE!

Single dose vs. multiple dose steady state studies: Guideline on the investigation of bioequivalence (2009) In certain cases when a single dose study cannot be conducted in healthy volunteers due to tolerability reasons, and a single dose study is not feasible in patients, conduct of a multiple dose study in patients may be acceptable

Single dose vs. multiple dose steady state studies: Guideline on the investigation of bioequivalence (2009) A multiple dose study as an alternative to a single dose study may also be acceptable if problems of sensitivity of the analytical method preclude sufficiently precise plasma concentration measurements after single dose administration. As Cmax at steady state may be less sensitive to differences in the absorption rate than Cmax after single dose, bioequivalence should, if possible, be determined for Cmax after the single dose administration (i.e. after the first dose of the multiple dose study) as a measure of peak exposure while extent of exposure can be based on demonstration of bioequivalence of AUC at steady state.

Design: Standardisation (EMEA 2009)
The test conditions should be standardised in order to minimise the variability of all factors involved except that of the products being tested. Therefore, it is recommended to standardise diet, fluid intake and exercise

Fasting or fed conditions (EMEA 2009)
The study should be conducted during fasting conditions unless the SPC recommends intake of the originator product only in the fed state. If the recommendation of food intake in the SPC is based on pharmacokinetic properties such as higher bioavailability, the bioequivalence study should be conducted in the fed state. Also if the recommendation of food intake is intended to decrease adverse events or to improve tolerability, it is recommended to conduct the bioequivalence study in fed state, although a bioequivalence study under fasting conditions could be acceptable if this has been adequately justified.

Bioequivalence : Blood sampling
1- Before drug administration to assess absence of assay interference or possible carryover 2- Single dose study : • about 10 samples • adequate to characterize absorption (before Tmax) • up until the LOQ • 4-5 terminal half-life after Tmax 3- Multiple dose study • 10 samples during the dosing interval

B4-Bioequivalence : Experimental design

Bioequivalence: experimental design
Parallel design Cross-over design

Randomly assigned to treatments
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)

Bioequivalence : Parallel design
- Advantage • no washout period (appropriate for long - acting drug ) • possible unequal numbers of subjects per treatment group • statistical analysis is still possible when subjects (animals) are lost during the experiment - Limits • more subjects are required

Bioequivalence: parallel design
Drug with very long terminal t1/2

Bioequivalence : experimental design
- 2x2 crossover - other crossover e.g. : AB, BA, AA, BB ( BALAAM design ) periods 1 2 A B groups or sequences

Bioequivalence : 2x2 crossover design (I)
Advantage decrease in the residual error, therefore reduction in the number of subjects Limits washout period required risk of an unequal carryover effect difficulties in analyzing the design if subjects are lost during the experiment

B5-Bioequivalence : The a priori Bioequivalence range

A priori Bioequivalence range
These are the two limits ( 1, 2 ) between which the 90 % CI interval of the ratio of the two product should be located in order to accept average B.E. To be defined by the clinician

Acceptance limits (EMEA 2009)
In studies to determine bioequivalence after a single dose, the parameters to be analysed are AUCt and Cmax For these parameters the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of %. Confidence intervals should be presented to two decimal places. To be inside the acceptance interval the lower bound should be ≥ and the upper bound should be ≤

Decision procedures in bioequivalence trials
BE not accepted BE not accepted 1 2 the 90 % CI of the ratio 80% +125% BE accepted 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 formulations qui seraient réellement différentes de 15-20% puissent être déclarées BE.

L’intervalle ce confiance du ratio doit être intégralement contenu dans l’intervalle d’équivalence

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

A priori Bioequivalence range (4)
For drug with a narrow therapeutic index (additive model) (multiplicative model)

B6-Bioequivalence sample size

Bioequivalence : sample size (I)
The number of subjects has not to be justified if the appropriate risk is controlled (consumer risk, 5 %) For economical and ethical reasons, the appropriate number of subjects must be calculated to avoid an excessively high producer risk

Bioequivalence : sample size (II) Information required to calculate the sample size
: The bioequivalence range ( ± 20 % )  : The consumer risk (5 % )  : The producer risk (e.g., 20 % ) ( the probability of rejecting bioequivalence when products are actually bioequivalent. Power is used only in planning the experiment, not as part of the statistical test )  : The error / (residual) variance 

Bioequivalence : sample size : multiplicative model
 = 5 % - Power 80 % 1 = 2 = 1.25 T / R CV % 1.10 exp (2) - 1 0.90 1.0 10 20 30 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%

B8-Bioequivalence : Characteristics to be investigated

BE Characteristics to be investigated
- AUC & Cmax, (no longer Tmax) - Others - How to calculate or obtain these relevant parameters • Curve fitting vs trapezoidal rule • Cmax: observed vs calculated

B9-Bioequivalence : Analytical techniques

Bioequivalence : analytical technique
Must be validated Case of a chiral drug An enantioselective assay may have to be used Pooled approach as a preliminary analysis

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

The test problem

Bioequivalence : the test problem
From a regulatory point of view the producer risk of erroneously rejecting bioequivalence is of no importance The primary concern is the protection of the patient (consumer risk) against the acceptance of BE if it does not hold true

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

Classical statistical hypothesis: drawback
F% Ref Test n=1000 n=1000 100 702 652 Statistically different for p  0.05 but actually therapeutically equivalent

Classical statistical problem : the drawback
F% Ref Test n=3 n=3 100 70 30 Not statistically different with p ≥ 0.05 but actually not therapeutically equivalent

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

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

Bioequivalence: the test problem
The appropriate hypothesis H01 (Ref -test) H02 (Ref -test) H0 q1 q2 inequivalent (Ref -test) H1 q1 q2 equivalent Observation

Bioequivalence: the test problem
The appropriate hypothesis q1 q2 (Ref -test) H01 H02 5% 5% two unilateral "t" tests Can we reject H01? Can we also reject H02? YES YES Bioequivalent

Bioequivalence : The test problem (2)
Multiplicative model (1) Ho : µT / µR < 1 or µT / µR > 2 (Bioinequivalence) H1 : 1 < µT / µR < 2 (B.E.) µT and µR : the expected medians for test and reference respectively 1 and 2 ( 0 <  < 1 < 2 ) : lower and upperlimits of the bioequivalence range (1 = 0.8, 2 = 1.25 )

Bioequivalence : the test problem The two one-sided test procedure
(XT - XR) - 1 t1 t 1 -  (  ) = s 2 / n 2 - (XT - XR) t2 t 1 -  ( ) = s 2 / n s : square root of the error mean square (ANOVA) n : number of subjects  : df associated with s

Decision procedures in bioequivalence trials
Regulatory point of view 1 A priori B.E. Range 2 BE accepted only the 90 % CI 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

Pharmacometric issues

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 to avoid 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

Le modèle statistique du crossover 2x2 (modèle linéaire à effets mixtes)
𝑌 𝑖𝑗𝑘 =𝜇+ 𝐹 (𝑗,𝑘) + 𝑃 𝑗 + 𝑆𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑘 + 𝑆𝐸𝑄 𝑘 + 𝜀 𝑖𝑗𝑘 Yijk The observation (AUC or Cmax) associated with the ith subject (nested in the kth sequence, during the jth period The population overall mean F(j,k) The direct fixed effect of the formulation associated with the jth period and the kth sequence . Pj The fixed effect of the jth period Subject ik the random effect of the ith subject nested in the the kth sequence SEQk The fixed effect of the kth sequence ; confounded with the direct group effect and also with a possible first-order carry-over of the formulation in the kth sequence which is administered at the (j-1)th period . εijk The residual (unexplained) error associated with the ith subject nested in the kth sequence during the jth period; it is the within–subject random error in observing Yijk; it is this error term that is used to compute the width of the 90% confidence interval

ANOVA 2x2 cross-over Selection of the appropriate ratio :
the choice of the appropriate error term

Bioequivalence : statistical analysis crossover design
L’effet séquence n’est plus à tester dans la nouvelle ligne directrice 2009

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 period effect
Not desirable Does not invalidate a cross-over design Origin : enzymatic induction, environment, equal carryover

The 2x2 cross-over design
the carryover effect

The carryover effect The direct drug effect is the effect that a drug produces during the period in which the drug is administered The carryover effect is the drug effect that persists after the end of the dosing period ("memory effect")

The carryover effect If the carryover effects are unequal, no unbiased estimate exists for the direct effects from both periods

The carryover effect 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

Equal vs. unequal cary-over effect
Period 1 Period 2 A B Equal carryover effect give a period effect Period 1 Period 2 A B 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.

Acceptance limits (EMA 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 (e.g. lévothyrox)
(Ln-transformed)

Conclusions (1) Personne ne conteste globalement l’intérêt des génériques 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 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) Aspects techniques
Sont généralement justifiés pour démontrer une BE: L’approche pharmacocinétique plutôt que pharmacodynamique et clinique Le choix de volontaires sains plutôt que des patients Sauf si on suspecte une interaction formulation*type de sujet La dose unique plutôt que des doses multiples Le nombre de sujets, même faible, si le risque statistique approprié (celui du patient) est contrôlé Sont discutables et méritent d’être discuté: La non démonstration statistique de la « substituabilité » (switchability) des formulations (princeps vs. génériques et génériques entre eux) Le choix, a priori, des intervalles d’équivalence qui doit rester une décision médicale prise dans l’intérêt du patient Le foisonnement en France des génériques et la fixation du risque de première espèce à 5%

Conclusions (3) 2-Aspects de gestion du risque
Est discutable et mérite d’être discutée la politique française de substitution Pour certains types de médicaments à marges thérapeutiques étroites (anti-épileptiques, anti-arythmiques….,) ou encore pour les populations à risque, le prescripteur devrait être le décideur par défaut 3-Les aspects industriels/BPF Les contrôles dans certains pays (Chine, Inde, Brésil..) 4-Tout ce qui tourne autour de l’observance et de la pharmacovigilance

A-Bioéquivalence: considérations techniques et scientifiques

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A-Bioéquivalence: considérations techniques et scientifiques

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