Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Assessment of Interchangeable Multisource Medicines, Kenya, August |2 | Bioequivalence in vivo comparison of products by means of volunteers serving as “in-vivo dissolution model” Bioequivalence studies: comparison of product characteristics to ensure therapeutic equivalence ‘biological quality control’

Assessment of Interchangeable Multisource Medicines, Kenya, August |3 | Regulatory requirements for BE studies single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers 90% CI AUC and Cmax: 80 – 125%

Assessment of Interchangeable Multisource Medicines, Kenya, August |4 | Regulatory requirements for BE studies Bioequivalence: Linear pharmacokinetics Non narrow therapeutic drug Non highly variable drugDecision based upon parent drug data Stereochemistry not an issue Decision based upon plasma concentrations

Assessment of Interchangeable Multisource Medicines, Kenya, August |5 | Regulatory requirements for BE studies Special cases: Dose- or time dependent pharmacokinetics Specific food recommendations Active metabolitesPro-drugs Enantiomers

Assessment of Interchangeable Multisource Medicines, Kenya, August |6 | Bioequivalence-non linear pharmacokinetics select the strength with the largest sensitivity to detect differences in the two products Goal: compare performance 2 formulations

Assessment of Interchangeable Multisource Medicines, Kenya, August |7 | Bioequivalence-non linear pharmacokinetics Linear PK: R T RT

Assessment of Interchangeable Multisource Medicines, Kenya, August |8 | Bioequivalence-non linear pharmacokinetics AUC/Cmax increase less than dose proportional exception: solubility !

Assessment of Interchangeable Multisource Medicines, Kenya, August |9 | Bioequivalence-non linear pharmacokinetics AUC/Cmax increase more than dose proportional

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-narrow therapeutic drugs Narrow Therapeutic Index Drugs

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-narrow therapeutic drugs ‘Critical dose drugs’ –Small changes in dose may cause Serious therapeutic failure Serious adverse events –Individual dose-titration needed (TDM) Narrow Therapeutic Index Drugs

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-narrow therapeutic drug Acceptance range for bioequivalence testing The 90%-CI should lie within the range of AUC-ratio C max -ratio In cases of NTI drugs the acceptance range may need to be tightened (0.9 – 1.11)

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-narrow therapeutic drug The EU position The current BE guideline does not specifically address NTI drugs Narrowing of BE acceptance range allowed

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-narrow therapeutic drug The Canadian position:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-narrow therapeutic drug Canadian guidance for NTI drugs AUC: 90%-CI within C max : 90%-CI within Studies in both fasted and fed state Steady-state studies on a case-by-case basis –C min : 90%-CI within

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – highly variable drugs

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – highly variable drugs Highly variable drugs What are HVD? HVD drugs and products How to establish BE HVD

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – highly variable drugs What are HVD? HVD are medicinal products which show high inter occasional variability: CV > 30% Occasion 1Occasion 2 Not the ANOVA CV!

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – highly variable drugs HVD drugs and products High Variable Drug High variability caused by intrinsic intra- indiviudual variability in the pharmacokinetic response of the active compound High Variable Product High variability caused by intra indiviudual variability in the pharmacokinetic caused by formulation effects

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – highly variable drugs How to establish HVD Problem: Difficult to establish bioequivalence with normal acceptance criteria (90 % CI) 45% CV=15% CV=30% N=88 subjects

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-highly variable drugs Increase number of subjects Multiple dose (steady-state) studies Replicate design to determine intra-individual variability - widen goal post How to establish HVD

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-highly variable drugs How to establish HVD Scaling an example: *  w0 is the SD at which the BE limits are permitted to be widened (set by an agency) *  wr is either the residual SD (ABE2) or the SD of the ref product (replicate design)

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-highly variable drugs % The Black Box Sw0=0.20 Sw0=0.25 Swr 80% 125%

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence-highly variable drugs SwrSw0=0.20Sw0=

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – metabolite Bioequivalence based on the metabolite Parent = pro-drug Analytical difficulties –too low concentration –unstable in matrix Short elimination half-life parent drug Metabolite contributes to the activity Pharmacokinetics non-linear (parent + metab.) Reasons:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – metabolite FORMATION RATE-LIMITED METABOLISM (IV) (FRL) ELIMINATION RATE-LIMITED METABOLISM (IV) (ERL)

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – metabolite Metabolite data can only be used if the Applicant presents convincing, state-of-the art arguments that measurements of the parent compound are unreliable. Further considerations (1): Cmax of the metabolite is less sensitive to differences in the rate of absorption than Cmax of the parent drug. when the rate of absorption is considered of clinical importance, bioequivalence should, if possible, be determined for Cmax of the parent compound, if necessary at a higher dose.

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – metabolite Metabolite is more reflective of metabolite formation, distribution and elimination. Further considerations (2): Measurement inactive metabolite can be rarely justified. When using metabolite data as a substitute for parent drug concentrations, the applicant should present data supporting the view that the parent drug exposure will be reflected by metabolite exposure dose. Bioequivalence based upon confidence interval approach.

Assessment of Interchangeable Multisource Medicines, Kenya, August | Bioequivalence – metabolite Example: metabolite: 90% CI AUC and C max within 80 – 125% but parent..!

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies Modified release (MR) oral dosage forms:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies MR dosage forms single unit formulations multiple unit formulations EC formulations

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies single dose, two-period, crossover, fasting Modified release (MR) oral dosage forms: Requested BE studies for enteric coated formulations: not statistical significant different 90% CI AUC and Cmax: 80 – 125% or single dose, two-period, crossover, fed 90% CI AUC and Cmax: 80 – 125% pH!

Assessment of Interchangeable Multisource Medicines, Kenya, August | Results of bioequivalence study obtained in bio-study for one strength to the other strengths based upon dose proportionality and dissolution data. Fed and fast bioequivalence studies normally no problem Regulatory requirements for BE studies EC formulations multiple unit formulations:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Results of bioequivalence study obtained in bio-study for one strength to the other strengths based upon dose dissolution data and proportionality, except for the enteric coating!! Fed study mostly problematic! Regulatory requirements for BE studies EC formulations single unit formulations:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies EC formulations single unit formulations:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies EC formulations single unit formulations:

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies single dose, two-period, crossover, fasting Modified release (MR) oral dosage forms: Requested BE studies for controlled release formulations: 90% CI AUC and Cmax: 80 – 125% single dose, two-period, crossover, fed 90% CI AUC and Cmax: 80 – 125% multiple dose, two-period, crossover, fasting - steady state conditions - EU, not FDA 90% CI AUC and Cmax: 80 – 125%; Cmin and PTF! - dose dumping -- FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002)

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies Cmax,ss AUCss Cmin,ss PTF

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies MR oral dosage forms: Single unit formulations: –Single dose study fasted state for every strength –Multiple dose study may be waived for lower strengths If a product concerns several strengths: Multiple unit formulations: –Single and multiple dose studies may be waived for lower strengths in case of identical granules or pellets In vitro dissolution studies

Assessment of Interchangeable Multisource Medicines, Kenya, August | Regulatory requirements for BE studies Fixed combination products… in vivo comparison vs. appropriate comparator combination (or separate comparator products in specific cases) general testing criteria apply to all active components bioequivalence criteria apply to all active compounds 90% CI AUC and Cmax: 80 – 125%

Assessment of Interchangeable Multisource Medicines, Kenya, August | End