44me Congrs International SFSTP 6 et 7 juin 2012

LA CONNAISSANCE SCIENTIFIQUE AU SERVICE DE LA QUALITE PRODUIT

Apports du Quality by Design et retours dexpriences

FDA recommendations for ANDAs based on QbD: A bioequivalence case study

Ethan Stier Deputy Director of Division of Bioequivalence II FDA, Office of Generic Drugs

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

FDA recommendations for ANDAs based on QbD: A bioequivalence case study

Proposal to use pAUC metrics to assess BE of Methylphenidate multiphasic modified release (MMR) formulations

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

Therapeutic Equivalence
Pharmaceutical Equivalence Bioequivalence

Therapeutic Equivalence
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 3

Therapeutic Equivalence
Generic product will have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling, and may be substituted for each other without adjustment in dose or other additional monitoring

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

Current FDA Acceptance Criteria for BE Studies

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

How to show that two drugs are bioequivalent

FDAs regulations define BE as lack of a significant difference in rate and extent to which drug becomes available at the site of action For systemically active drugs Cmax AUC

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

Current acceptance criteria for BE studies

The 90% confidence intervals of the geometric mean test/reference (T/R) Cmax and AUC ratios should fall within the limits of 80-125% Metrics are Cmax AUC0-t AUC We also evaluate Tmax qualitatively (not statistically) Not a continuous variable Value determined by sampling times
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 7

A Complex Product which Meets BE Criteria but Deemed not TE

12 10 8 6 4 2 0 0 10 20 Time (hr) 30 40 test ref

Ethan Stier

P lasm aC o nc. (ng/m l)

44me Congrs International SFSTP 6-7 Juin 2012

Quality Target Product Profile

ICH Q8(R2) Definition QTPP : A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

Methylphenidate case study

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

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MMR formulation design

Multiphasic modified release (MMR) products formulations contain an immediate-release (IR) and delayed-release (DR) and/or extended release (ER) portions, where The IR portion is necessary for rapid onset of activity; The DR or ER portion is necessary to sustain activity
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 11

Marketed MPH MMR products

Concerta tablet ER core with an IR overcoat Metadate CD capsule Formulated as 30% IR, 70% ER Ritalin LA capsule dose as IR beads dose as enteric-coated, DR beads
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 12

Mean plasma profiles Concerta qd vs IR MPH tid

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

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Clinical response throughout day following single Concerta dose

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

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MPH MMR products

Given once daily, in the morning MPH does not accumulate to steady-state PK / PD models show that peak response achieved at about same time as peak MPH plasma concentrations For Concerta, maximal response occurs 2 hrs post-dosing, sustained throughout day

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

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FDA Proposal for pAUC BE Metrics for MPH MMR Formulations

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

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Proposed BE metrics for MMR products

Propose to use 4 metrics instead of 3 Present: Cmax AUC0-t AUC Proposed: Cmax AUC0-T AUCT-t AUC AUC0-T should compare T & R exposure responsible for early onset of response AUCT-t should compare T & R exposure responsible for sustained response All metrics should met BE limits (80-125)
Where T is product-specific time, t is last PK sampling time
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 17

Using AUC0-3h for BE studies of generics to MPH multiphasic products

In fasting subjects The IR MPH Tmax [mean S.D.] is 2 0.5 h; 2 hr is also time at which maximal response [compared to placebo] is achieved; By 3 hr, expect that 95% of patients should achieve maximal early onset of response Mean 2 S.D. = 95% of population response 95% of subjects should achieve maximal early onset of response by 2 h + [2 x 0.5 h] = 3 h
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 18

Proposal for pAUC BE metrics for generics to MPH multiphasic products

For fasting BE studies Cmax AUC0-3h AUC3h-t AUC For fed BE studies Cmax AUC0-4h AUC4h-t AUC Early pAUC should compare T & R exposure associated with response onset Later pAUC should compare T & R exposure associated with sustained response
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Summary and Conclusions

Ethan Stier

44me Congrs International SFSTP 6-7 Juin 2012

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For Detailed QBD examples

Quality by Design Example for Generic Modified Release Drug Products (http://www.aaps.org/uploadedFiles/Content/Sections_an d_Groups/Regional_Discussion_Groups/Sept%20presen tation.pdf) Quality by Design for ANDAs: An Example for Modified Release Dosage Forms (http://www.fda.gov/downloads/Drugs/DevelopmentAppr ovalProcess/HowDrugsareDevelopedandApproved/Appr ovalApplications/AbbreviatedNewDrugApplicationANDA Generics/UCM286595.pdf)
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 21

Summary and Conclusions

Present FDA BE study acceptance criteria may not be adequate for some drugs formulated as MMR products FDA proposes using two pAUCs for BE studies of MMR products formulated to achieve rapid onset of response and sustained response The first pAUC will compare T & R early exposure The second pAUC will compare T& R later exposure
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 22

Summary and Conclusions

FDA proposes selecting the sampling time for the first pAUC to ensure that 90-95% of subjects will have achieved the optimal early onset of response The objective is to ensure that the proposed generic to a multiphasic MR product, once approved, will be switchable with its corresponding reference
Ethan Stier 44me Congrs International SFSTP 6-7 Juin 2012 23

References
The FDA proposed to use pAUC metrics to assess BE of methylphenidate MMR products at the FDAs Pharmaceutical Sciences and Clinical Pharmacology Advisory Committee in April 2010

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44me Congrs International SFSTP 6-7 Juin 2012

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THANKS!
Barbara M. Davit PhD, JD Dale P Conner Pharm D Devrat Patel Pharm D Stephanie Kim PhD Partha Chandaroy PhD Andre Raw PhD

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44me Congrs International SFSTP 6-7 Juin 2012

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