I’am the Spine-Adjust me! I’am the Bulk-Adjust me! DPS_7x10_IBT_Template.indd Pharmaceutical Science and Technology 200 DRUGS AND THE PHARMACEUTICAL SCIENCES VOLUME 200 about the book… With 45 chapters that cover all of the major technical and clinical topics in a Common Technical Document registration, including summaries, quality of the drug substance and dosage form, S E C O N D EDiTiO N SECOND nonclinical studies and clinical trials, this Second Edition provides a roadmap for International Conference on Harmonisation (ICH) and other technical and regulatory requirements for global EDiTiON filings in the US, EU, Japan and elsewhere. This book provides a comprehensive overview of all of the scientific areas involved in the development and registration of new drug and other pharmaceutical products intended for International registration internationally. I n The book provides an essential practical toolkit for: t e • regulatory affairs staff involved with writing, assembling, compiling, publishing and r submitting registration files n a Pharmaceutical • the professional staff in the ‘data provider’ teams who design the studies and provide t i the technical and scientific reports and documentation—the pharmaceutical R&D staff, o n chemical manufacturing, pharmaceutical manufacturing, analytical development, a packaging development, QC, clinical trials staff, medical and scientific affairs, l medical affairs, and project management. P h Product Registration • r eviewers in the regulatory agencies a r about the editors... m ANTHONY C. CARTWRIGHT is a Pharmaceutical Regulatory Consultant, Harpenden, UK. Tony a c Cartwright is involved in numerous professional organizations including the Royal Pharmaceutical e Society of Great Britain, the Drug Information Association and The Organisation for Professionals u in Regulatory Affairs, where he chairs their Lifelong Learning Committee. He was formerly Chair of tic TES: the European CPMP Quality Working Party. He was an active participant in working groups and O a N conferences of the International Conference on Harmonisation, particularly involved in guidelines l X P X on stability testing and impurities. He has authored over 30 scientific and technical publications X r X and book chapters. He is the Co-editor of Informa Healthcare’s Pharmaceutical Product Licensing: o D: Requirements for Europe and the first edition of International Pharmaceutical Product Registration. d E u S VI BRIAN R. MATTHEWS, Ph D, is Senior Director, EU Registration and Authorised Representative for c E t R Alcon Laboratories and is based in the UK. He is involved with a number of professional associations R TE such as the Parenteral Drug Association, The Organisation for Professionals in Regulatory Affairs A e D and the Royal Pharmaceutical Society of Great Britain. He is also involved in a number of standards g X committees within the British Standards Institution, the European Standards Committee and the is XX International Standards Organization where his particular interests include methods of sterilization, tr XX animal materials used in the manufacture of medical devices, contact lens care products, intraocular a D: t E lenses, irrigation solutions, viscosurgical products and Braille for application to pharmaceutical io AT E labelling. He is also a member of committees within the British Pharmacopoeia relating to pharmacy n R C and to microbiology. Brian has written a number of papers on a wide range of topics relating to E T pharmaceutical legislation. He is on the editorial boards for the Regulatory Affairs Journal (Pharma) A D and (Medical Devices) and the European Journal of Parenteral and Pharmaceutical Sciences. In addition X to co-editing Pharmaceutical Product Licensing: Requirements for Europe and the first edition of Cartwright X X X International Pharmaceutical Product Registration he is also the author of Pharmaceutical Excipients: • X A Manufacturer’s Handbook. Matthews edited by ME: A Printed in the United States of America H8176 N Anthony C. Cartwright LE FI Brian R. Matthews XX R: E N G SI E D Cartwright_978-1420081764.indd 1 7/24/09 1:39:10 PM PANTONE 202 C International Pharmaceutical Product Registration Cartwright_978-1420081764_TP.indd 1 7/24/09 1:39:33 PM S E C O N D EDi t iO N International Pharmaceutical Product Registration edited by Anthony C. Cartwright Pharmaceutical Regulatory Consultant Harpenden, U.K. Brian R. Matthews Alcon Laboratories Hemel Hempstead, U.K. Cartwright_978-1420081764_TP.indd 2 7/24/09 1:39:34 PM IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= DRUGSANDTHEPHARMACEUTICALSCIENCES ASeriesofTextbooksandMonographs ExecutiveEditor JamesSwarbrick PharmaceuTech,Inc. Pinehurst,NorthCarolina AdvisoryBoard LarryL.Augsburger HarryG.Brittain UniversityofMaryland CenterforPharmaceuticalPhysics Baltimore,Maryland Milford,NewJersey JenniferB.Dressman RobertGurny UniversityofFrankfurtInstituteof UniversitedeGeneve PharmaceuticalTechnology Geneve,Switzerland Frankfurt,Germany JeffreyA.Hughes AnthonyJ.Hickey UniversityofFloridaCollege UniversityofNorthCarolina ofPharmacy SchoolofPharmacy Gainesville,Florida ChapelHill,NorthCarolina VincentH.L.Lee AjazHussain USFDACenterforDrug Sandoz EvaluationandResearch Princeton,NewJersey LosAngeles,California JosephW.Polli KinamPark GlaxoSmithKline PurdueUniversity ResearchTrianglePark WestLafayette,Indiana NorthCarolina JeromeP.Skelly StephenG.Schulman Alexandria,Virginia UniversityofFlorida Gainesville,Florida ElizabethM.Topp UniversityofKansas YuichiSugiyama Lawrence,Kansas UniversityofTokyo,Tokyo,Japan PeterYork GeoffreyT.Tucker UniversityofBradford UniversityofSheffield SchoolofPharmacy RoyalHallamshireHospital Bradford,UnitedKingdom Sheffield,UnitedKingdom IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= For information on volumes 1–151 in the Drugs and Pharmaceutical Science Series, Pleasevisitwww.informahealthcare.com 152. PreclinicalDrugDevelopment,editedbyMarkC.RoggeandDavidR.Taft 153. PharmaceuticalStressTesting:PredictingDrugDegradation,editedbyStevenW.Baertschi 154. HandbookofPharmaceuticalGranulationTechnology:SecondEdition,editedbyDilipM. Parikh 155. PercutaneousAbsorption:Drugs–Cosmetics–Mechanisms–Methodology,FourthEdition, editedbyRobertL.BronaughandHowardI.Maibach 156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A. Meyer and Rachel F. Tyndale 157. PharmaceuticalProcessScale-Up,SecondEdition,editedbyMichaelLevin 158. Microencapsulation:MethodsandIndustrialApplications,SecondEdition,editedbySimon Benita 159. NanoparticleTechnologyforDrugDelivery,editedbyRamB.GuptaandUdayB.Kompella 160. SpectroscopyofPharmaceuticalSolids,editedbyHarryG.Brittain 161. DoseOptimizationinDrugDevelopment,editedbyRajeshKrishna 162. HerbalSupplements-DrugInteractions:ScientificandRegulatoryPerspectives,editedby Y.W.FrancisLam,Shiew-MeiHuang,andStephenD.Hall 163. Pharmaceutical Photostability and Stabilization Technology, edited by Joseph T. Piechocki andKarlThoma 164. EnvironmentalMonitoringforCleanroomsandControlledEnvironments,editedbyAnne MarieDixon 165. Pharmaceutical Product Development: In Vitro-ln Vivo Correlation, edited by Dakshina MurthyChilukuri,GangadharSunkara,andDavidYoung 166. NanoparticulateDrugDeliverySystems,editedbyDeepakThassu,MichelDeleers,andYash- wantPathak 167. Endotoxins:Pyrogens,LALTestingandDepyrogenation,ThirdEdition,editedbyKevinL. Williams 168. GoodLaboratoryPracticeRegulations,FourthEdition,editedbyAnneSandyWeinberg 169. GoodManufacturingPracticesforPharmaceuticals,SixthEdition,editedbyJosephD.Nally 170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of Poorly Water-soluble Drugs,editedbyDavidJ.Hauss 171. HandbookofBioequivalenceTesting,editedbySarfarazK.Niazi 172. AdvancedDrugFormulationDesigntoOptimizeTherapeuticOutcomes,editedbyRobert O.WilliamsIII,DavidR.Taft,andJasonT.McConville 173. Clean-in-PlaceforBiopharmaceuticalProcesses,editedbyDaleA.Seiberling 174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition, edited by MaikW.JornitzandTheodoreH.Meltzer 175. ProteinFormulationandDelivery,SecondEdition,editedbyEugeneJ.McNallyandJayneE. Hastedt 176. AqueousPolymericCoatingsforPharmaceuticalDosageForms,ThirdEdition,editedby JamesMcGinityandLindaA.Felton 177. DermalAbsorptionandToxicityAssessment,SecondEdition,editedbyMichaelS.Roberts andKennethA.Walters 178. PreformulationSolidDosageFormDevelopment,editedbyMojiC.AdeyeyeandHarryG. Brittain 179. Drug-DrugInteractions,SecondEdition,editedbyA.DavidRodrigues 180. Generic Drug Product Development: Bioequivalence Issues, edited by Isadore Kanfer and LeonShargel 181. Pharmaceutical Pre-Approval Inspections: A Guide to Regulatory Success, Second Edi- tion,editedbyMartinD.HynesIII 182. PharmaceuticalProjectManagement,SecondEdition,editedbyAnthonyKennedy 183. ModifiedReleaseDrugDeliveryTechnology,SecondEdition,Volume1,editedbyMichael J.Rathbone,JonathanHadgraft,MichaelS.Roberts,andMajellaE.Lane IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= 184. Modified-ReleaseDrugDeliveryTechnology,SecondEdition,Volume2,editedbyMichael J.Rathbone,JonathanHadgraft,MichaelS.Roberts,andMajellaE.Lane 185. ThePharmaceuticalRegulatoryProcess,SecondEdition,editedbyIraR.BerryandRobert P.Martin 186. Handbook of Drug Metabolism, Second Edition, edited by Paul G. Pearson and Larry C. Wienkers 187. PreclinicalDrugDevelopment,SecondEdition,editedbyMarkRoggeandDavidR.Taft 188. ModernPharmaceutics,FifthEdition,Volume1:BasicPrinciplesandSystems,editedby AlexanderT.FlorenceandJu¨rgenSiepmann 189. Modern Pharmaceutics, Fifth Edition, Volume 2: Applications and Advances, edited by AlexanderT.FlorenceandJu¨rgenSiepmann 190. NewDrugApprovalProcess,FifthEdition,editedbyRichardA.Guarino 191. Drug Delivery Nanoparticulate Formulation and Characterization, edited by Yashwant PathakandDeepakThassu 192. PolymorphismofPharmaceuticalSolids,SecondEdition,editedbyHarryG.Brittain 193. Oral Drug Absorption: Prediction and Assessment, Second Edition, edited by Jennifer J. Dressman,HansLennernas,andChristosReppas 194. BiodrugDeliverySystems:Fundamentals,Applications,andClinicalDevelopment,edited byMarikoMoristaandKinamPark 195. PharmaceuticalProcessEngineering,SecondEdition,editedbyAnthonyJ.HickeyandDavid Ganderton 196. Handbook of Drug Screening, Second Edition, edited by Ramakrishna Seethala and Litao Zhang 197. PharmaceuticalPowderCompactionTechnology,SecondEdition,editedbyMetinCelik 198. HandbookofPharmaceuticalGranulationTechnology,DilipM.Parikh 199. PharmaceuticalPreformulationandFormulation,SecondEdition:APracticalGuidefrom CandidateDrugSelectiontoCommercialDosageForm,editedbyMarkGibson 200. InternationalPharmaceuticalProductRegistration,SecondEdition,editedbyAnthonyC. CartwrightandBrianR.Matthews IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= InformaHealthcareUSA,Inc. 52VanderbiltAvenue NewYork,NY10017 (cid:1)C 2009byInformaHealthcareUSA,Inc. InformaHealthcareisanInformabusiness NoclaimtooriginalU.S.Governmentworks PrintedintheUnitedStatesofAmericaonacid-freepaper 10987654321 InternationalStandardBookNumber-10:1-4200-8176-4(Hardcover) InternationalStandardBookNumber-13:978-1-4200-8176-3(Hardcover) Thisbookcontainsinformationobtainedfromauthenticandhighlyregardedsources.Reprintedmaterialisquoted withpermission,andsourcesareindicated.Awidevarietyofreferencesarelisted.Reasonableeffortshavebeen madetopublishreliabledataandinformation,buttheauthorandthepublishercannotassumeresponsibilityfor thevalidityofallmaterialsorfortheconsequenceoftheiruse. 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Matthews.–2nded. p.;cm.– (Drugsandthepharmaceuticalsciences,v.200) Includesbibliographicalreferencesandindex. ISBN-13:978-1-4200-8176-3(hardcover:alk.paper) ISBN-10:1-4200-8176-4(hardcover:alk.paper) 1. Pharmaceuticaltechnology–Standards. 2. Drugs–Testing–Standards. 3. Drugs–Lawandlegislation. I.Cartwright,A.C (AnthonyC.),1940-II.Matthews,Brian(BrianR.) III.Series:Drugsandthepharmaceutical sciences,v.200. [DNLM:1. Technology,Pharmaceutical–standards. 2. ClinicalTrialsasTopic–standards. 3. Legislation,Drug. 4. QualityControl. W1DR893Bv.2002009/QV778I6032009] RS189.I622009 615’.19–dc22 2009015392 For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department, 52VanderbiltAvenue,7thfloor,NewYork,NY10017. VisittheInformaWebsiteat www.informa.com andtheInformaHealthcareWebsiteat www.informahealthcare.com IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= Preface THEOBJECTIVESANDSCOPEOFTHENEWEDITION The International Conference on Harmonisation of Technical Requirements for Registration ofPharmaceuticalsforHumanUse(ICH)CommonTechnicalDocument(CTD)providesfora harmonizedstructureandformatfornewpharmaceuticalproductregistrationapplications.The CTDformathasbeenadoptedinthethreeICHregionsoftheUnitedStates,theEuropeanUnion, and Japan and is increasingly used elsewhere in the world. The chapters in the new second editionofthisbookcoverallthemajortechnicalandclinicaltopicsthatareincludedunderthe mainheadingsintheCommonTechnicalDocument—theModule2summariesandoverviews, Module 3 Quality, Module 4 Nonclinical Safety, and Module 5 Clinical Efficacy. One chapter dealswiththeparticularnationalandregionspecificadministrativeandprescribinginformation in Module 1 in terms of application forms, health professional, and patient information, etc.; otherchaptersdealwiththeelectronicCTDandenvironmentalriskassessment. Thisbook,therefore,providesacomprehensiveoverviewofallthescientificareasinvolved inthedevelopmentandregistrationofnewdrugandotherpharmaceuticalproductsintended forregistrationinternationally.Thebookiswrittentomeettheneedsofbothregulatoryaffairs staffinvolvedinwriting,assembling,compiling,publishing,andsubmittingregistrationfiles, and the professional staffs in the “data provider” teams who design the studies and pro- vide the technical and scientific reports and documentation—the pharmaceutical R&D staff, chemical manufacturing, pharmaceutical manufacturing, analytical development, packaging development,QC,clinicaltrialsstaff,medicalandscientificaffairs,medicalaffairs,andproject management. We have also included one or two chapters dealing with “cutting edge” issues where the regulatorypolicyisnotyetfullyagreed.Thus,wehaveincludedchapterson“Modelingand MedicinalProductR&D,”andacopyofanAgencefranc¸aisedese´curite´ sanitairedesproduits desante´ (Afssaps)WorkingGrouponNonclinicalInnovationdocumententitled“Recommen- dationsforToxicologicalEvaluationofNanoparticleMedicinalProducts.” Medicinalproductscoversuchanenormousrange—frominvivodiagnosticagentstoradio- pharmaceuticalstospecialistbiologicalandbiotechnologicalproducts—sothattocoverindetail the needs of all types of product would have required writing an encyclopedia rather than a singlebook.Inevitably,theeditorshavehadtoomitsomeaspectsinrelationtothesespecialist products. PROGRESSININTERNATIONALHARMONIZATION Since the first edition of this book, there have been enormous changes in the technical and scientific requirements for the dossier, as the work of the ICH has continued to devise and approvenewguidelinesinthecategoriesofQuality,Safety,Efficacy,andMultidisciplinary.The CTD harmonized structure and modular format for new medicinal product registration files that were adopted in San Diego, is now the obligatory format in the European Union (EU), Japan,Canada,Switzerland,andAustralia.ItistherecommendedformatintheUnitedStates. AsmentionedinChapter1ofthisbook,derivativesoftheCTDarebecomingwidelyaccepted inotherregionsoftheworld. THECTD—ACOMMONFORMAT,NOTAHARMONIZEDCONTENTFORSUBMISSIONS Enormous efforts have been expended by the staffs of the regulatory agencies and the phar- maceutical industry in the work of the ICH, and this has achieved a remarkable degree of IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= viii Preface harmonizationinmanyscientificandtechnicalareasofthedossier.Despitethistherearestill national differences in the content of submissions not only in Module 1, the administrative andprescribinginformation,butalsoinotherareasofthedossier.Thesearisefromdifferences inregulatorypracticeandprocedures,differentpracticesofmedicineandpharmacy,anddif- ferences in access to diagnostic and therapeutic procedures. We are, however, still far from a genuinelyglobalsingleregistrationdossier.Thechapterauthorshavetriedtocapturesomeof thesedifferenceswhereverfeasibletohelpthoseplanningtomarkettheirproductsindifferent regionsoftheworld. INCREASEDCOOPERATIONBETWEENAGENCIESBASEDONICH MutualRecognitionAgreementsbetweenagenciesinrelationtoGoodManufacturingPractice (GMP)areinoperationbetweentheEUandCanada,Australia,NewZealand,Switzerland,and Japan.Arrangementsexistbetweenmanycountries(includingtheICHmembers)forexchange ofpharmacovigilanceanddefectinformation. TheconfidentialityarrangementsbetweentheEUandtheFDAnowallowforexchangeof informationonlegalandregulatoryissues,scientificadvice,orphandrugdesignation,inspec- tionreports,marketingauthorizationprocedures,andpostmarketingsurveillance.InSeptember 2004,theEuropeanMedicinesAgency(EMEA)andtheFoodandDrugsAdministration(FDA) institutedapilotprogramofparallelscientificadvicemeetingsforsponsorstoobtainadviceon scientificissuesduringthedevelopmentphaseofnewmedicinalproducts.Orphanindication productsandpediatricproductshavebeentargetedinparticular. Under the aegis of the Transatlantic Economic Council, the EU and FDA have reviewed waysinwhichcooperationcanreduceadministrationandenablethemtosharebestregulatory practices. This has been followed by an EMEA announcement of proposals for a EU–US– AustralianpilotprogramtomakemoreefficientuseofglobalGMPinspectionresources. Bilateral and trilateral collaboration has increased in 2008. Health Canada has agreed to exchangeinformationwiththeEuropeanCommissionandEMEAabouttheauthorizationand safetyofdrugs.CanadaandAustraliahavestartedtheirparallelreviewprojectforbiologicals (originallylaunchedin2006). Allofthishasonlybeenpossiblebasedonthepriorworkthathasbeendoneinharmonization ofregulatoryrequirementsandinthedevelopmentoftheCTDformat ofthedossierinICH, whicharediscussedinthisbook. SPREADINGTHEICHMESSAGE—THEICHGLOBALCOOPERATIONGROUP The ICH-affiliated and other developed countries, which have adopted the CTD format (the UnitedStates,EU,Japan,Canada,Switzerland,andAustralia),compriseintotalapproximately 15%ofthecurrent(2008)worldpopulationof6650millionpeople.TheICHGlobalCooperation Group(GCG)wasformedonMarch11,1999asasubcommitteeoftheICHSteeringCommittee. ItspurposeistomakeinformationavailableonICH,ICHactivities,andanyICHguidelineto awidergroupofcountries. RegionalHarmonizationInitiatives A number of regional harmonization initiatives (RHIs) have been set up where a geographic groupingofcountriesharmonizestechnicalandscientificrequirementsandinsomecasesthe format of submissions for member countries. These groups have been invited to designate permanentrepresentativestotheGCG.Theycurrentlycomprise: (cid:1) (cid:1) Asia-PacificEconomicCooperation(APEC):21countriesintheAsia-Pacificregion. AssociationofSoutheastAsianNations(ASEAN):BruneiDarussalam,Cambodia,Indone- (cid:1) sia,Laos,Malaysia,Myanmar,Philippines,Singapore,ThailandandVietnam. GulfCooperationCountries(GCC):SaudiArabia,Kuwait,UnitedArabEmirates,Oman, (cid:1) Bahrain,QatarandYemen. PanAmericanNetworkonDrugRegulatoryHarmonisation(PANDRH):Argentina,Bar- bados, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Guatemala, Jamaica, Mexico, Panama,TrinidadandTobagoandVenezuela. IHBK042-FM IHBK042-Cartwright July18,2009 15:23 CharCount= Preface ix (cid:1) SouthAfricanDevelopmentCommunity(SADC):Angola,Botswana,DemocraticRepub- licofCongo,Lesotho,Malawi,Mauritius,Madagascar,Namibia,Seychelles,SouthAfrica, Swaziland,Tanzania,ZambiaandZimbabwe. The regional groups review the applicability of the ICH guidelines in their own specific countries. Particular topics of interest include the ICH stability guideline, GMP guidances, requirements for bioavailability and bioequivalence studies, clinical trials, export/import of medicines,traditionalmedicines,andmarketsurveillance.Manyofthesetopicsarecoveredin thisbook. DRUGSAFETYANDRISKMANAGEMENT In2008,boththeEMEAandtheFDAplacedanincreasingemphasisondrugsafetyandrisk management.TheFDAlauncheditsSafetyFirstinitiativetostrengthenitsinternalpoliciesto improvedrugsafetyreview. In Europe, the EMEA consulted on proposals to strengthen its pharmacovigilance system, and in December 2008, brought forward a new “pharma package” of draft legislation for consideration. This includes adding a new legal requirement for a risk management system for each new medicinal product. Adverse drug reporting and periodic safety update reports (PSURs) would be made more proportionate to the risks, and all data would be added to theEudravigilancedatabase.AnewPharmacovigilanceRiskAssessmentAdvisoryCommittee wouldbesetuptoassesspharmacovigilancedata. Currentrequirementsforpharmacovigilanceandpostmarketingaresummarizedinchapters inthisbook. OUTSOURCINGOFR&D,CLINICALTRIALS,ETC. There are currently single-digit percentage increases in drug sales in the United States and Europe,astherate ofnewdrugapproval (particularly intheUnitedStates)slowsdown and thereisincreasingcompetitionfromgenerics.Companiesaresheddingstaffandoutsourcing R&D,manufacture,etc.,increasinglytoAsiaandChina.Again,theexistenceofinternationally acceptedguidelines(suchasthosediscussedinthisbook)enablesworktobeoutsourcedand carriedouttoacceptableagreedstandards. Inaddition,manypharmacompaniesareintegratingclinicaltrialsoutsidetheICHregions into global clinical development programs. These trials conducted according to ICH Good Clinical Practice and reported in accordance with ICH guidelines (as discussed in this book) willhaveaccesstowell-trainedphysiciansandalargenumberoftreatment-na¨ıvepatientsat significantly lower cost. Such global trials will enable clinical data to be obtained on patients withdifferentethnicbackgroundsandwillhelpfacilitateacoordinatedregistrationandreduce the“druglag”indelayedregistrationoutsidetheICHregions. NewChemicalEntityorNewBiotechnologicalProducts It is evident that a huge effort has been put into the harmonization discussions and negotia- tionsbetweenthemajorregulatoryagenciesandthepharmaceuticaltradeassociationsinthe United States, Japan, and Europe. This book reviews the key international requirements for registeringaNewActiveSubstanceproductcontainingaNewChemicalEntity(NCE)ornew biological/biotechnologicalentityandtotrytoexplainhowtheserequirementscouldbemetby definedprogramsofwork.Thebookisintendedtocoverallthemajorscientificandtechnical topicsinsucharegistrationfile. Whereharmonizationhasalreadytakenplace(eitherundertheauspicesofICHorelsewhere), theauthorsoftheindividualchaptersofthisbookhavereviewedprogressandhavesuggested themaindirectionsthatthisislikelytotake.Programsofdrugdiscoveryanddevelopmentfor new drug products usually take place over a 10- to 12-year period, and thus studies started nowwilloftennotbethesubjectofasubmissiontotheauthoritiesforsomeyears.Anastute researchlaboratoryoradevelopmentmanagerisonewhoidentifiesandanticipatesthetrends indevelopmentofscientificandtechnicalthinkingandhowthesemayeventuallybetranslated into legal rules and guidelines for registration of medicinal products so that the company’s