FDA's Experience on IVIVC – Generic Drugs - PQRI

FDA’s <strong>Experience</strong> on IVIVC –Generic DrugsBarbara M. Davit, Ph.D., J.D., DirectorDivision of Bioequivalence II, Office of Generic DrugsCenter for Drug Evaluation and Research (CDER)United States Food and Drug Administration (US-FDA)barbara.davit@fda.hhs.govPQRI Workshop on Application of IVIVC in Formulation DevelopmentCo-sponsored with FDA/FIP/AAPS/USPSept. 5-6, 2012Bethesda, MD1

Outline• Review of Guidance for Industry on IVIVC• Uses of in vitro-in vivo correlation (IVIVC) ingeneric drug development• Case studies• Use of in vitro-in vivo relationships (IVIVR)in generic drug development• Summary and conclusions2

Review of FDA Guidance forIndustry on IVIVC3

FDA Guidance for Industry• Extended-Release Oral Dosage Forms:Development, Evaluation, and Applicationof In Vitro/In Vivo Correlations (9/97)• Content– Recommendations for developing the IVIVC– IVIVC applications4

Recommendations fordeveloping the IVIVC• Level A correlations are most useful• Level C correlations can be useful in earlydevelopment stages• Level B correlations are least useful• Develop correlation with 3 or moreformulations with differing release rates– Two may be acceptable in some situations• In vivo study = single-dose crossover5

Recommendations fordeveloping the IVIVC• Develop in vitro dissolution methodologythat can adequately discriminate amongformulations• Evaluate both internal and externalpredictability• For a generic product, bioequivalence(BE) to the reference product should beestablished prior to IVIVC study6

Uses of IVIVC in generic drugdevelopment7

Case studies9

Case AObjective: support dissolution specificationApplicant’s approach• Formulations tested were to-bemarketed(TBM) generic, a pilotformulation, and an IRformulation• Determined Level A correlation• Assessed internal predictability• Concluded that IVIVC datasupported proposed dissolutionspecificationsFDA’s assessment• Applicant submitted only asummary report of IVIVC data;full report was needed to makeassessment• A manufacturer other than theapplicant produced the IRformulation used in the IVIVC• No external predictability datasubmittedOutcome: applicant withdrew amendment forother reasons 10

Case BObjective: challenge results of a failed BE studyApplicant’s approach• Used lower strength of TBMproduct line as faster-releasingformulation• Used higher strength of TBMproduct line as slower-releasingformulation• Performed Level A correlation• Assessed internal and externalpredictabilityFDA’s assessment• Deemed external predictabilitystudy as acceptable• Concluded that dissolution ratesof the two formulations did notsupport conclusion that one wasfast-releasing and one wasslow-releasing• Rejected the IVIVC proposalOutcome: applicant conducted a new in vivostudy which met BE acceptance criteria 11

Case CObjective: support changes in dissolution specificationsApplicant’s approach• Manufactured slow-, mid- andfast-releasing formulations ofthe drug product• Used these formulations for invitro and in vivo studies• Developed a Level A correlation• Back-calculated ACU and Cmaxvalues from dissolutionspecification limitsFDA’s assessment• Confirmed that the backcalculatedCmax and AUC,determined using the proposeddissolution specifications, metBE limits of 80-125%Outcome: FDA concurred with the proposed changesto the dissolution specifications 12

Case DObjective: support proposed changes to dissolutionmethodApplicant’s approach• Developed a Level A correlationusing the applicant’s TBMformulation and the referenceproduct formulation• Did not assess internal orexternal predictabilityFDA’s assessment• IVIVC development isformulation specific• It is not appropriate to usedifferent test and referenceformulations, each from adifferent manufacturer• No internal or externalpredictability data weresubmittedOutcome: applicant withdrew the amendment 13

Case EObjective: to support a Level 3 site changeApplicant’s approach• Manufactured slow-, mid- andfast-releasing formulations• Used formulations for in vitroand in vivo studies• Conducted a Level A correlation• Assessed internal and externalpredictabilityFDA’s assessment• Internal and externalpredictability were not confirmed• The “fast” release formulationdissolution profiles did not differfrom those of the “slow” releasedissolution profiles, despite thefact that the two formulationsshowed marked differences inAUC and CmaxOutcome: applicant conducted an in vivo BEstudy to support the Level 3 site change 14

IVIVR15

Uses of IVIVR• Not as robust as an IVIVC• Can be an important feature a Quality byDesign (QbD) approach with respect to– Generic drug development– Prediction of performance of commercialbatches– Assessment of post-approval changes16

IVIVRExample below taken from “QbD for ANDAs,An Example for Modified-Release DosageForm”, developed by staff from FDA’s Officeof Generic Drugs17

IVIVR example• Reference product and prototypeformulation F-1 used to optimizedissolution method (USP Apparatus 3, 10dpm, 250 mL pH 6.8 phosphate buffer)• Deconvoluted PK profile of pilotformulation F-1 (not BE to reference) toobtain fraction of in vivo drug release18

IVIVR example• Established IVIVR (y = 1.1114x – 0.1382)to predict plasma concentration profiles• Developed prototypes F-2 and F-3• Conducted dissolution studies of F-2, F-3,convoluted data to predict mean in vivo PKprofiles• Simulated virtual trial simulations viamodeling19

IVIVR example• IVIVR and simulation studies suggestedthat F-2 would be bioequivalent toreference• In vivo BE studies of F-2 and F-3 againstreference confirmed results of IVIVR andsimulation studies• Thus, IVIVR was used to select theoptimal formulation for development20

IVIVR example summaryUse RLD and prototype F1to optimize dissolutionmethodSet dissolution methodDeconvolute to calculatefraction of in vivo drugreleaseEstablish IVIVRUse IVIVR to developprototypes F2, F3Conduct dissolution studiesof F2 and F3Convolute to predict PKprofiles and simulate BEstudy resultsSelect formulation(s)for pivotal BE studiesConduct in vivo studies toconfirm BE of F2 and F3Use results of in vivo BEstudy to confirm F todevelop for marketing21

Uses of IVIVR• To perform convolution of the in vitro datafor reference and prototype genericformulations• To predict outcome of BE studies usingvarious prototype formulations• To establish a linkage between exhibit andcommercial batches22

Summary and conclusions23

Summary and conclusions• FDA Guidance for Industry providesrecommendations for properly establishingIVIVC of generic modified-release oraldrug products• IVIVC can be used to support some postapprovalchanges, and changes indissolution method/specifications, formodified-release generic drug products24

Summary and conclusions• Very few submissions to FDA’s Office ofGeneric Drugs (from 1996-2012)contained IVIVC data, and most were notacceptable• FDA’s Office of Generic Drugs proposesusing IVIVR as part of a QbD approach fordevelopment of generic modified-releaseformulations25

References• FDA Guidance for Industry, Extended-Release OralDosage Forms: Development, Evaluation, andApplication of In Vitro/In Vivo Correlations, QbD forANDAs,http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070239.pdf• QbD for ANDAs, An Example for Modified-ReleaseDosage Form,http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf26

Acknowledgements• Angelica Dorantes, Ph.D.• John Duan, Ph.D.• Gregory Geba, M.D.• Paramjeet Kaur, Ph.D.• Tahseen Mirza, Ph.D.• Sandra Suarez-Sharp, Ph.D.• Raj Uppoor, Ph.D.• Lawrence Yu, Ph.D.

Thank you for your attention!28