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© 2007-2015Accell Clinical Research, LLC

New Russian Drug Law: Changes Concerning Clinical Studies and

Marketing Authorization and Their Implications

Dr. Natalia NayanovaDirector, Clinical Operations

Accell Clinical Research

ClinicalTrialsInnovationProgrammeOctober22-23,2015Frankfurt,Germany

© 2007-2015Accell Clinical Research, LLC

Russian Pharmaceutical Market Turnover, Dynamics & Forecast

7,2 9,5 11,8 12,6 14,6 16,1 17,4 18,3 19,7 21,3 23,3 25,7

0

5

10

15

20

25

30

2007 2008 2009 2010 2011 2012 2013 2014(forecast)

2015(forecast)

2016(forecast)

2017(forecast)

2018(forecast)

blnUSD

2

Source: DSMGroupandIMSHealthviaDeloitte

© 2007-2015Accell Clinical Research, LLC

Russia in the List of Countries by Pharmaceutical Market Size

2008 2013 20171 USA USA USA2 Japan China China3 China Japan Japan4 France Germany Brazil5 Germany France Germany6 Italy Brazil France7 Canada Italy Italy8 United Kingdom UnitedKingdom Russia9 Spain Canada UnitedKingdom10 Brazil Spain Canada11 Mexico Russia India12 Australia India Spain13 Russia Mexico Mexico

3

(Source:IMSHealthviaDeloitte)

© 2007-2015Accell Clinical Research, LLC

Russian Clinical Trial Market: Facts and Figures

4

Clinicaltrialsapprovedin3months

Centralizedhealthcare,specializedhospitals

Lowmigrationrates,thushighretention

Loweraccesstostate-of-the-arttreatmentprotocols

Treatment-naïvepatientsinmanyindications

Experiencedandhighlyqualifiedinvestigators

Fasterrecruitment

HighqualityofdataGCPincorporatedinlegislation

Inourrecent7clinicalstudies,enrollmentratesatAccell’ssiteswere

1,4to7timeshigherthanintherestoftheworld

© 2007-2015Accell Clinical Research, LLC

Russian Clinical Trial Market: No. of Clinical Trials by Phase

25 43 64 39 34 37

129 86 87 111 91 84

289232

327396

373 338

47

38

7548

2824

2009 2010 2011 2012 2013 2014

PhaseI PhaseII PhaseIII PhaseIV

Total:490

399

553594

526483

5

Source:OrangePaper— clinicaltrialsinRussiabySynergy

© 2007-2015Accell Clinical Research, LLC

Russian Clinical Trial Market: FDA & EMEA Acknowledgement

6

2008 2009 2010 2011 2012 2013 2014

8197 101 102 102

114 111

34

820

3421

53 45

Total ofthem:usingRussiandata

2008 2009 2010 2011 2012 2013 2014

85

142

5167

87101 104

35 27 2232

48

8664

Total ofthem:usingRussiandata

Source:OrangePaper— clinicaltrialsinRussiabySynergy

NewDrugsApprovedbyFDA

NewDrugApplicationsApprovedbyEMEA

Year FDAaudits

NAI VAI OAI

2008 20 13 7 0

2009 15 11 4 0

2010 10 9 1 0

2011 3 2 1 0

2012 7 6 1 0

2013 4 2 2 0

Total 36 24 12 0

*NAI=noactionindicatedVAI=voluntaryactionindicatedOAI=officialactionindicatedSource:FDA

ClinicalInvestigatorInspectionsbyFDAinRussia

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Regulatory Framework in Russia

7

3months

MinistryofHealthand

CentralEthicsCommittee

parallelsubmissions40workdays(2months)

LocalEthicsCommittee• Presentatmostsites• LECapprovalrequired

werepresent2-4weeks

Import/exportlicense• RequiredforanyIMP,

materialsoriginatingfromoutsideRussia

• Requiredforexportofallmaterials,samplesoutsideRussia5workdays

1month 1month

Feasibilityanddossier

preparation

IMPimport

Siteinitiation

Firstpatientin

5monthstotal

© 2007-2015Accell Clinical Research, LLC

Legislative Framework for Medicinal Products in Russia

Ø FederalLaw# 61-FZ dated April12,2010 “Oncirculationofmedicinalproducts”Ø FederalLaw#429-FZamendsLaw#61-FZØ Majorityofchangesto#61-FZlawtookeffectonJuly1,2015;

certainprovisionswilltakeeffectJanuary1,2017Ø NationalStandardofRussianFederation«GoodClinical

Practice» GOST-R 52379-200 (effectiveSeptember27,2005)

Ø December23,2014— anAgreementonCommonPrinciplesandRulesofDrugCirculationintheEurasianEconomicUnionwassigned,andwillbeineffectfollowingratificationbyallpartiesbutnoearlierthanJanuary1,2016

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General Regulatory Approach to Changes to 61-FZ Drug Law

Ø “OldLaw”hadsomeinherentflawsintheareasof:Ø DefinitionsØ CorrelationwithglobalbestpracticesØ LegalframeworkforgenericdrugsØ Inconsistencywiththecurrentstateofthepharmaceuticalmarketanditsdevelopment

Ø “NewLaw”approvedafterconsultationsandreviewbytheindustryandaimstooptimizethequalityofregulatoryprocessesandenhancetheexperienceofcompaniesapplyingforMarketingAuthorizationinRussia

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Improvements to Existing Definitions

PreviouslyØ Pharmaceuticalsubstance

Ø Withlimiteddefinitionoforigin

Ø Originalmedicinalproduct

Ø Reproduced(generic)medicinalproduct

CurrentlyØ Pharmaceuticalsubstance

Ø Anysubstancewithpharmacologicalactivityregardlessoforigin

Ø Referencemedicinalproduct

Ø Reproduced(generic)medicinalproductØ Includesbiologicaland

therapeuticequivalenceconfirmation

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New Definitions in 2015 LawØ NewLawaddsdefinitionsfor:

Ø OrphanmedicinalproductØ BiologicalmedicinalproductØ Biotechnology-basedmedicinalproductØ Immunobiological drugsØ GenetherapymedicinalproductØ HomeopathicdrugsØ Biosimilar drugsØ Therapeuticequivalency

Ø Additionofnewdefinitionscreatesnewregulatorypathwaysforcertaincategoriesofdrugs

Ø Formerlawdidnotdefinethesecategoriesofdrugseparately

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Biosimilars VS. Generic

ØNewlawforthefirsttimeintroducesthedifferencebetween“generic”and“biosimilar”medicinalproducts

ØDifferenceinhandlingmarketingauthorizationbytheregulator

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Interchangeable Medicinal Products

Ø DefinitioninitiatedbyFederalAntimonopolyService(FAS)toimprovecompetitionforfederalprocurementofdrugs

Ø StartingJanuary1,2018informationaboutinterchangeabilityofdrugsissubjecttoinclusiontotheFederalDrugRegistry

Ø Interchangeabilityisdeterminedbythepanelofexpertsduringthemarketingauthorizationdossierreview

Ø FordrugsregisteredpriorDecember22,2014interchangeabilitymustbedefinedbyDecember31,2017

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GxP

ØMinistryofHealthnowresponsibleforapprovalandimplementationofØGLPØGCPØGMPØGoodStorageandTransportPracticeØGoodDistributionPracticeØGoodPharmacyPracticeØGoodPharmacovigilancePractice

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© 2007-2015Accell Clinical Research, LLC

Clinical Trials for Medicinal Products

Ø Previously,clinicaltrialsweresubjecttoreviewintheframeworkoftheMarketingAuthorizationsubmission

Ø Keychange:clinicaltrialapplicationreviewprocess(ECandMOH)isexcludedfromthemarketingauthorizationprocess

Ø Standaloneapproachtoclinicaltrialdossierreviewsimplifiesandstreamlinestheapplicationandreviewprocess

Ø ClinicaltrialsconductedinpartorinwholeinRussiaarestillarequirementforMarketingAuthorizationapproval

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© 2007-2015Accell Clinical Research, LLC

Scientific Advice: New Opportunity

PreviouslyØ Nomechanismforscientific

advicewaspresent;nofeedbackfromMinistryofHealth

CurrentlyØ Scientificadviceoptionis

availableunderthenewlawforØ PreclinicalstudiesØ ClinicaltrialsØ MarketingauthorizationØ Quality,efficacy,safetyreview

Ø ForfeeserviceofMinistryofHealth

Ø Writtenresponsetoinquiriesforscientificadvice

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© 2007-2015Accell Clinical Research, LLC

Marketing Authorization Dossier Composition Changes

Ø DefinitionforMAHolderisaddedtotheLaw(previouslyabsent)

Ø Effective01.01.2016;Format:StandardTechnicalDocumentØ AdministrativesectionØ Chemical,pharmaceutical,biologicalsectionØ PharmacologyandtoxicologysectionØ Clinicalsection

Ø FormatshouldbeestablishedbytheMinistryofHealthØ Lawstipulatesadetailedlistofrequireddocumentsgenerallyaswellasallowedexceptions

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© 2007-2015Accell Clinical Research, LLC

Marketing Authorization Timelines

PreviouslyØ GeneralMApathway— 210

businessdays;clockstopsforQ&A

Ø ExpeditedMApathway—60businessdaysØ Reproduced(generic)drugs

Ø Confirmationoffederalregistration— 90businessdays

CurrentlyØ GeneralMApathway— 160

businessdays;clockstopsforQ&A

Ø ExpeditedMApathway—80businessdaysØ OrphanindicationsØ FirstthreegenericdrugsØ Exclusivelypediatricdrugs

Ø Confirmationoffederalregistration— 60businessdays(asof01.01.17)

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© 2007-2015Accell Clinical Research, LLC

Marketing Authorization: New Exception Examples, Generics

ØGenericdrugs:Ø AllowstoprovidescientificliteraturereviewofpreclinicalstudiesofthereferencedrugINLIEUoftheSponsor’sownpreclinicalstudiesofthegenericdrug

Ø ClinicalStudyReportforBioequivalencystudiesonlyinlieuofthefullclinicaltrialprogram(previouslyfullprogramofclinicalstudieswasrequired)

Ø Effective01.01.2016:drugmakerscanapplyforgenericmarketingauthorizationin§ 4yearsfromreferenceproductregistration— forbiosimilardrugs

§ 6yearsfromreferenceproductregistrationforgenericdrugs

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© 2007-2015Accell Clinical Research, LLC

Marketing Authorization: New Exception Examples, Orphan DrugsØOrphandrugs:

Ø NewMAapplicationpathwayfororphandrugsØ AllowstheSponsortoprovidereportsofpreclinicalandclinicalstudiesperformedoutsideofRussianFederationinaccordancewithGCPandGLP

ØOrphanandbiotechnology-baseddrugs:Ø MAholdersarenowrequiredtoprovideforafeetheirreferenceproductforthepurposeofclinicaltrials,atcostnotinexcessofregisteredpriceinthecountry(effective01.01.2016)

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New Additional Provisions for MA Cancellation

ØLackofregistereddrugonthemarketforover3yearsfromregistrationdate

ØLackofPVreportingØRefusalofMAholdertoamendMAwithnewlydiscoveredinformationonrisksoutweighingthebenefits

ØVoluntaryMAcancellationbytheMAholder

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PharmacovigilanceØ DefinitionsaddedtothenewLawfor

Ø PharmacovigilanceØ RiskManagementPlan

Ø Regulatorwillanalyzeallmonitoredinformation(safety,efficacy,risks)notonlyinRussiabutglobally

Ø MAholdersarerequiredto:Ø Collect,analyze,retainandreporttotheRegulatoryAuthorities

informationonsideeffects,SAE,SUSAR,drug-druginteraction,tolerabilityandotherfactorsposingpotentialhealththreats

Ø Effective01.01.16frequencyofPVGreportingchangesto:§ Onceevery6monthsforthefirsttwoyearspost-registration§ Annuallyforthesubsequentthreeyears§ Onceevery5yearsthereafter

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Implications of Changes to Drug Law for Foreign Sponsors

Ø DruglawcorrelateswithlatestinternationalstandardsØ TransparencyØ RobustdefinitionsØ MinistryofHealthScientificAdvisoryoption.

Ø Expandeddefinitionsofbiological,biosimilar,immunobiological,andotherdrugscreatednewregulatorypathways.

Ø Reductionofoveralltimetomarketforthedrugs.Ø Streamlinedclinicaltrialapplicationprocess.Ø Competitivelandscapeforparticipationinthefederalprocurement

processfordrugmakers.Ø OpensuptheRussianmarketforeasieraccessforpharmaceutical

companiesspecializedingeneric,orphanandpediatricdrugdevelopment.

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© 2007-2015Accell Clinical Research, LLC

Thank you for attention!

Dr.NataliaNayanovaDirector,ClinicalOperations

Natalia.Nayanova@accellclinical.comOffice:+7-812-332-1420Mobile:+7-921-864-2517