臨床藥理學(xué)課件：Chapter 5 New drug research and clinical trials

Chapter5NewdrugresearchandclinicaltrialsClinicalPharmacologyguidetolearningTomastertheconceptofnewdrugsandnewdrugdevelopment,clinicaltrialsofnewdrugs,clinicaltrialprinciplesandrelevantprovisions.ToFamiliarwithnewdrugdiscoveryapproachesandpreclinicalstudies.Understandingofdrugclinicaltrialqualitymanagementstandards,newdrugapplicationandregistration.

DefinitionofdrugsDrug:Asubstanceusedinthediagnosis,treatment,orpreventionofadiseaseorasacomponentofamedicationSection1.Thenewdrugdiscoveryandpreclinicalstudies

DefinitionofNewdrugs

Newdrugsaredrugsthathavenotlistedintheterritoryofchina.Including:Thatathomeandabroadarenotproducedbythecreationofdrugs,knowntochangethedosageform,tochangethewayofdrugadministrationortoaddnewindications,madeanewcompoundpreparationisalsointhemanagementofnewdrugs.Researchanddevelopmentofnewdrugs,includingdrugdiscovery,preclinicalresearchandclinicalresearch.Newdrugapplication

Newdrugapplicationisanapplicationforregistrationofdrugsthatarenotlistedintheterritoryofchina.Including:Thatatdomesticandinternationalhavenotproducedthecreationofdrugs,knowntochangethedosageformofdrugs,drugdeliverywaystochangeorincreasethenewindications.Genericdrugapplications

Genericdrugapplications,referstotheproductionofnationalFDAhasapprovedthelistingofthenationalstandardofdrugapplications,butthebiologicalproductsaccordingtothenewdrugapplication.Newdrugregistration

Newdrugregistration:9subcategoriesoftraditionalChinesemedicine,6subcategoriesofchemicaldrugs,biologicalproducts,15subcategories.I.NaturalProducts

ApproachofDrugDiscoveryNaturalplants,animals,microorganisms,marineorganismsandotherpharmacologicalactivitiesarestilloccupiesanimportantpositioninthedrugdiscovery.Atpresent,themostcommonlyuseddrugsarederivedfromnaturalproductsandtheirderivatives,antibiotics,vitamins,alkaloids,steroidsandotherdrugswhichareextractedfromnaturalresources,isolatedactiveingredients.

INaturalProducts

ApproachofDrugDiscoverypaclitaxel;taxinol(紫杉醇，泰素）新藥發(fā)現(xiàn)途徑與臨床前研究（一）天然產(chǎn)物一、新藥發(fā)現(xiàn)途徑紫杉醇（taxol，泰素）1963年，美國(guó)化學(xué)家M.C.Wani和MonreE.Wall首次從一種生長(zhǎng)在美國(guó)西部大森林中的太平洋杉（PacificYew）樹皮和木材中分離到了紫杉醇的粗提物，篩選實(shí)驗(yàn)表明對(duì)離體培養(yǎng)的鼠腫瘤細(xì)胞有很高活性1971年，他們與杜克大學(xué)的化學(xué)教授姆克法爾合作，通過X-射線分析確定了該活性成份的化學(xué)結(jié)構(gòu)為一種四環(huán)二萜化合物1989年，美國(guó)國(guó)家癌癥研究所指定百時(shí)美施貴寶公司為合作伙伴，共同對(duì)紫杉醇進(jìn)行開發(fā)，使其產(chǎn)業(yè)化1992年12月，F(xiàn)DA批準(zhǔn)紫杉醇為晚期卵巢癌的治療藥物，現(xiàn)已廣泛應(yīng)用于多種惡性腫瘤2006年總銷售額已達(dá)37億美元，高居世界抗癌藥物之首

ApproachofDrugDiscoveryArteannuinDoublehydrogenartemisininartemetherArtesunate新藥發(fā)現(xiàn)途徑與臨床前研究青蒿素1970年代，我國(guó)科學(xué)家從中草藥黃花蒿中分離出抗耐氯喹惡性瘧原蟲、結(jié)構(gòu)類型新穎的過氧化物倍半萜類抗瘧藥青蒿素對(duì)青蒿素的進(jìn)一步結(jié)構(gòu)優(yōu)化，以期解決其生物利用度低、溶解性差和復(fù)發(fā)率高的缺點(diǎn)。用四氫硼鈉還原青蒿素得到的雙氫青蒿素比青蒿素療效高一倍，雙氫青蒿素的甲基化產(chǎn)物蒿甲醚抗瘧活性強(qiáng)于青蒿素10～20倍，雙氫青蒿素制成的琥珀酸單酯鈉鹽（青蒿琥酯)可制備注射劑，用于危重的腦型瘧疾。青蒿素、蒿甲醚、青蒿琥酯均已收入中國(guó)藥典并進(jìn)入國(guó)際市場(chǎng)。復(fù)方蒿甲醚由蒿甲醚和本芴醇兩種成分組成，進(jìn)一步解決了蒿甲醚作用時(shí)間短、復(fù)發(fā)率高等缺點(diǎn)。新藥發(fā)現(xiàn)途徑與臨床前研究青蒿素1994年，中瑞雙方正式簽署專利開發(fā)許可協(xié)議，昆明制藥負(fù)責(zé)生產(chǎn)蒿甲醚，新昌制藥負(fù)責(zé)生產(chǎn)本芴醇。諾華公司負(fù)責(zé)復(fù)方蒿甲醚在國(guó)際上的開發(fā)研究工作，組織了由國(guó)際著名科學(xué)家和中方合作者參與的研究隊(duì)伍，在全球20多個(gè)國(guó)家開展了復(fù)方蒿甲醚的國(guó)際多中心臨床試驗(yàn)2001年，WHO正式將復(fù)方蒿甲醚等青蒿素類復(fù)方藥物作為一線抗瘧藥物在全球范圍內(nèi)推廣，并于次年將復(fù)方蒿甲醚列入其基本藥物核心目錄。2002年，復(fù)方蒿甲醚的全球需求僅為10萬劑，2005年就達(dá)到3200萬劑。復(fù)方蒿甲醚已獲得中、美等49個(gè)國(guó)家和地區(qū)的發(fā)明專利，并在80個(gè)國(guó)家和地區(qū)獲得藥品注冊(cè)。

INaturalProducts

ApproachofDrugDiscoveryIsolationofnaturecompoundfromherbalortraditionalremediesorsynthesizetheirderivatives.morphinefromopiumpoppy,罌粟alkaloidsforcancertherapy,Atropinefromnightshade顛茄Digitoxinanddigoxinfromfoxgloves毛地黃

INaturalProducts

ApproachofDrugDiscoveryFromstudyofendogenousagentsinanimals.insulinfromanimalpancreas,hirudinfromleech,水蛭素與水蛭AncrodfromthevenomoftheMalayanpitviper

降纖酶與馬來亞蝮蛇蛇毒降纖酶II.Accidentaldiscovery

ApproachofDrugDiscoveryIncidentalfindingsincludenonroutineprocessesandclinicalapplications."WhenIwokeupjustafterdawnonSeptember28,1928,Icertainlydidn'tplantorevolutioniseallmedicinebydiscoveringtheworld'sfirstantibiotic,orbacteriakiller,"Flemingwouldlatersay,"ButIsupposethatwasexactlywhatIdid.In1928,theBritishyoungbacterialscientistFleminginthestudyofStaphylococcusaureusintheexperiment,foundthatpenicillin.II.Accidentaldiscovery

ApproachofDrugDiscovery

Byserendipity:luckandintuitionpenicillin,1928byAlexanderFleming,Discoveryofsideeffectsofthetherapeuticusefulnessofasideeffectsofadrug.Sulfonylureasasaoralhypoglycaemicdrugsfromtheuseofsulfonamidesinpatientswithtyphoidfever,Sildenafil(Viagra)aspenileerectionagentfromthedevelopmentofantianginalagentIIIMetabolitesofdrugs

ApproachofDrugDiscoveryPharmacokineticstudieshavefoundthatsomeofthedrugsinthebodytoplayaroleintheconversionprocess,someofwhichareconvertedintoactivemetabolitesplayarole.IIIMetabolitesofdrugs

ApproachofDrugDiscoveryTheactivemetaboliteofacetophenetidin乙酰氨基酚isacetylaminophenol對(duì)非那西丁.TheactivemetaboliteofBenzodiazepine苯二氮卓isoxazepam奧沙西泮ProcainemetaboliteofN-acetylprocaineisstillactiveIVCombinationofexperience

chemistryandAppliedPharmacology

ApproachofDrugDiscoveryScreeningforactivecompounds,chemicalsynthesisofitsanalogues,pharmacologicalactivitydetection,animalandclinicaltrials.IVCombinationofexperience

chemistryandAppliedPharmacology

ApproachofDrugDiscoveryV.Computeraideddrugdesign

ApproachofDrugDiscovery

ApproachofDrugDiscovery

Whilstrandomscreeningandserendipityremainimportantinthediscoveryofnewdrugs,newknowledgeoftheroleofreceptors,enzymes,ionchannelsandcarriermoleculesinbothnormalphysiologicalprocessesanddiseasenowpermitsamorefocusedapproachtodrugdesign.Usingadvancesincombinatorialchemistry,biotechnology,genomics,highoutputscreeningandcomputer-aideddrugdesign,newdrugscannowbeidentifiedmorerationally.DefinitionofclinicaltrialObjectivesofclinicaltrialsPhasesofclinicaltrialsConductsofclinicaltrialsWhatAreClinicalTrials?Alsoknownasclinicalstudies,toevaluatetheeffectivenessandsafetyofmedicationsormedicaldevicesbymonitoringtheireffectsonlargegroupsofpeople.Clinicaltrialsarestudiesperformedwithhumansubjectstotestnewdrugsorcombinationsofdrugs,newapproachestosurgeryorradiotherapyorprocedurestoimprovethediagnosisofdiseaseandthequalityoflifeofthepatient.WhyAreClinicalTrialsImportant?

Clinicaltrialstranslateresultsofbasicscientificresearchintobetterwaystoprevent,diagnose,ortreatdiseaseinhumansThemorepeopletakepart,thefasterwecan:AnswercriticalresearchquestionsFindbettertreatmentsandwaystopreventdiseaseObjectivesofclinicaltrialsTodeterminewhetherthepharmacologiceffectsseeninhumansconfirmpredictionsderivedfromeffectdatafromanimalsToshowthatthepharmacologicactionsleadtotherapeuticallyusefuleffects.Todemonstratethatthedrugissafeenoughtobeusedinhumans.

ApprovalForTestingInHumans

Totestanewdrugexperimentallyinhumans,asponsormustfirstfileInvestigationalNewDrugApplication(IND)臨床研究申請(qǐng)inUSA.OrClinicalTrialApplicationsforInvestigationalMedicinalProductsinUK.INDprogramisthemeansbywhichapharmaceuticalcompanyobtainspermissiontoshipanexperimentaldrugtoclinicaltrialsbeforeamarketingapplicationforthedrughasbeenapproved.

HistoricalHighlightsofDrugTrials

1909:PaulEhrlich–Arsphenamine(Salvarsan,606,usedtotreatsyphilisandtrypanosomiasis.梅毒和錐蟲病)1929:AlexanderFleming-Penicillin1935:GerhardDomagk-Sulfonamide磺酰胺1944:Schatz/Bugie/Waksman–StreptomycinBy1950,theBritishMedicalRes.Councildevelopedasystematicmethodologyforstudying&evaluatingtherapeuticinterventionsBasicprinciplesofclinicaltrial1.Randomization2.Rationality3.Representative4.

ReplicationBasicprinciplesofclinicaltrial1.Randomization1).Simplerandomization

2).Stratificationrandomization3).

BlockrandomizationClinicalTrialPhasesPhaseItrials(FirstinHuman,FIH):healthyvolunteers,Smallgroupfor1sttimetoevaluatesafety,determinesafedosagerange&identifysideeffectWhatdosageissafe?Howshouldtreatmentbegiven?Howdoestreatmentaffectthebody?ClinicalTrialPhasesPhaseItrials(FirstinHuman,FIH):healthyvolunteers,Smallgroupfor1sttimetoevaluatesafety,determinesafedosagerange&identifysideeffectWhatdosageissafe?Howshouldtreatmentbegiven?Howdoestreatmentaffectthebody?

PreclinicalstudyofnewdrugNewchemicalentitiesaretestedinanimalstoinvestigatetheir

pharmacology,toxicology,pharmacokineticsandpotential

efficacyinordertoselectdrugsofpotentialvalueinhumans.Preclinicalstudyofnewdrugs,includingpreparationtechnology,physicalandchemicalproperties,purity,testingmethods,prescriptionscreening,dosageforms,stability,qualitystandards,pharmacology,toxicology,animalpharmacokineticsandsoon.Section2.Clinicaltrialstagingofnewdrugs

PreclinicalstudyofnewdrugPHASEITheinitialstudiesofdrugsinhumansusuallyinvolvehealthy

malevolunteersunlesstoxicityispredictable(e.g.cytotoxic

agents,murinemonoclonalantibodies).Thefirstdosetobe

administeredtohumansisusuallyafractionofthedosethat

producedanyeffectinthemostsensitiveanimalspecies

tested.Subjectiveadverseevents,clinicalsigns,haematology,biochemistry,urinalysisandelectrocardiographyareusedto

assesstolerability.

PreclinicalstudyofnewdrugPHASEIDependingonthepreclinicaldata,further,

morespecificevaluationsmaybeappropriate.Thestudiesare

placebocontrolledtoreducetheinfluenceofenvironmentand

normalvariability.Ifthedoseiswelltolerated,ahigherdose

willbeadministeredeithertoadifferentsubjectinaparalleldesign,ortothesamegroupinanincrementedcrossoverdesign.TypesofPhaseItrials1.SingleAscendingDosestudies:smallgroupsofpatientsaregivenasingledoseofthedrugwhiletheyareobservedandtestedforaperiodoftime.Iftheydonotexhibitanyadversesideeffects,andthepharmacokineticdataisroughlyinlinewithpredictedsafevalues,thedoseisescalated,andanewgroupofpatientsisthengivenahigherdose.Thisiscontinueduntilpre-calculatedpharmacokineticsafetylevelsarereached,orintolerablesideeffectsstartshowingup(atwhichpointthedrugissaidtohavereachedtheMaximumtolerateddose(MTD)Dosetolerability1.StartingDose:thefirstdoses(chosenwithdatafromanimals)aresmallenoughsothatnoeffectsareexpected.

EscalationSchemeForBothElements,ConflictBetween

Caution/Safetyvs.Efficiency/EfficacyTypesofPhaseItrials

2.MultipleAscendingDosestudies:areconductedtobetterunderstandthepharmacokinetics&pharmacodynamicsofmultipledosesofthedrug.Inthesestudies,agroupofpatientsreceivesmultiplelowdosesofthedrug,whilstsamples(ofblood,andotherfluids)arecollectedatvarioustimepointsandanalyzedtounderstandhowthedrugisprocessedwithinthebody.Thedoseissubsequentlyescalatedforfurthergroups,uptoapredeterminedlevel.2.最大劑量的確定方法：以臨床應(yīng)用的同類藥（或結(jié)構(gòu)接近的藥物）單次最大劑量；采用臨床前動(dòng)物長(zhǎng)期毒性試驗(yàn)中引起癥狀或臟器可逆性損害的劑量的1/10；采用臨床前動(dòng)物急性毒性試驗(yàn)的最大耐受劑量的1/5~1/2。第五節(jié)新藥臨床試驗(yàn)有關(guān)規(guī)定一、I期臨床試驗(yàn)（一）人體耐受性試驗(yàn)標(biāo)準(zhǔn)體重由動(dòng)物a到動(dòng)物b的mg·kg-1

劑量折算表（表中數(shù)值為換算系數(shù)Rab）動(dòng)物品種小鼠b倉(cāng)鼠b大鼠b豚鼠b家兔b家貓b獼猴b比格犬b狒狒b微型豬b成人b標(biāo)準(zhǔn)體重/kg0.020.080.150.41.82.53.010.012.020.060.0表面積/m20.00660.0160.0250.050.150.20.250.50.60.741.62體重系數(shù)0.08980.08620.08860.09210.10140.10860.12020.10770.11450.10040.1057系數(shù)S35681212.51220202737小鼠a1.000.6000.5000.3750.2500.2400.2500.1500.1500.1110.081倉(cāng)鼠a1.671.000.8330.6250.4170.4000.4170.2500.2500.1850.135大鼠a2.001.201.000.7500.500.4800.5000.3000.3000.2220.162豚鼠a2.671.601.331.000.6670.6400.6670.4000.4000.2960.216家兔a4.002.402.001.501.000.9601.000.6000.6000.4440.324家貓a4.172.502.081.561.041.001.040.6250.6250.4630.338獼猴a4.002.402.001.501.000.9601.000.6000.6000.4440.324比格犬a(chǎn)6.674.003.332.501.671.601.671.001.000.7410.541狒狒a6.674.003.332.501.671.601.671.001.000.7410.541微型豬a9.005.404.503.382.252.162.251.351.351.000.730成人a12.337.406.174.633.082.963.081.851.851.371.00注：例1已知150g（標(biāo)準(zhǔn)體重）大鼠用5mg.kg-1，求成人（標(biāo)準(zhǔn)體重）的用藥劑量。查表2，大鼠a行，成人b列的Rab=0.162，故成人的劑量=Db.Rab=d*0.162=0.81mg.kg-1。例2已知20g（標(biāo)準(zhǔn)體重）小鼠用4mg.kg-1，求8g（標(biāo)準(zhǔn)體重）犬的用藥劑量。查表2，小鼠a行，犬b列的Rab=0.150，故犬的劑量=Db.Rab=4*0.150=0.600mg.kg-1。例3已知8kg（標(biāo)準(zhǔn)體重）比格犬用00.68mg.kg-1，求22g小鼠、38g老齡鼠的用藥劑量。（1）查表2，犬a(chǎn)行，小鼠b列的Rab=6.67，故20g小鼠的劑量=Db.Rab=0.68*6.67=4.536mg.kg-1；（2）現(xiàn)22g小鼠與標(biāo)準(zhǔn)體重相差不到20%，按體重用4.536mg.kg-1，基本可行。根據(jù)標(biāo)準(zhǔn)體重W標(biāo)=20g，實(shí)際體重Wb=22g，B=22/20=1.1，查表3，Sb=0.969，故劑量=Db’.Rab.Sb=0.68*6.67*0.969=4.395mg.kg-1，與前劑量相差不到3%；（3）38g老齡鼠：根據(jù)B=38/20=1.9，查表3，Sb=0.807，故劑量=Db’.Rab.Sb=0.68*6.67*0.807=3.660mg.kg-1，該劑量也可用于31~46g的老齡鼠。

標(biāo)準(zhǔn)體重由動(dòng)物a到動(dòng)物b的mg·kg-1

劑量折算表（表中數(shù)值為換算系數(shù)Rab）TypesofPhaseItrials

3.Foodeffect:ashorttrialdesignedtoinvestigateanydifferencesinabsorptionofthedrugbythebody,causedbyeatingbeforethedrugisgiven.Thesestudiesareusuallyrunasacrossoverstudy,withvolunteersbeinggiventwoidenticaldosesofthedrugondifferentoccasions;onewhilefasted,andoneafterbeingfed.Methodsofdetermingtheinitialdoseofmedicineifthereisthesameclinicaltolerancetestdata,1/2ofitstheinitialamountwasasinitialdose.asimilardrugclinicaltolerancetestdata,the1/4ofinitialamount

wasasinitialdose.asimilardrugclinicaleffectivetestdata,the1/10ofeffectiveamount

wasasinitialdose.Methodsofdetermingtheinitialdoseofmedicinenorelevantdatainclinicaltrials,theresultswasfollowingavailablepreclinicalanimaltestingprojections.Blackwellmethod:theinitialdosedoesnotexceed1/600ofLD50ofsensitiveanimalor1/60ofminimumeffectivedose.Modified

Blackwellmethod:1/600ofLD50or1/60oftoxicdoseintwokindanimal.Dollerymethod:1%~2%ofeffectivedoseofmostsensitiveanimalor1/10ofclinicaltreatmentdoseofsimilardrugs.Methodsofdetermingmaximumdoseofmedicineasinglemaximumdoseofthesimilarclinicaldrugwasasthemaximumdose.1/10ofdosewhichcausedsymptomoforganorreversibledamageduringthelong-termtoxicityinpreclinicalanimaltestwasasthemaximumdose.1/5to1/2ofthemaximumtolerateddoseoftheacutetoxicitytestinpreclinicalanimaltestwasasthemaximumdose.Metabolicstudies Identifyingmetabolitesinhumansthatwerenotdetectedinanimalsisveryimportant.Suchmetabolitesmightrequireadditionalanimaltestingfortheirpharmacologic,toxicologicandcarcinogenicactivity.

Inter-speciesdifferencesindrugpropertiesAUCvaluesinplasmaforIododeoxydoxorubicin

(I-Dox)anditsmetaboliteiododeoxydoxorubicinol(I-Dox-ol)inMouse&HumansatEqui-ToxicDoses MouseHuman

I-Dox 5.0 0.3

I-Dox-ol1.2 4.0

(metabolite)

PreclinicalstudyofnewdrugPHASEI

PreclinicalstudyofnewdrugPHASEIIPhaseIIstudiesareusuallyconductedinasmallnumberof

patientsbyspecialistsintheappropriateareatoexploreefficacy,

toleranceandthedose–responserelationship.Ifitisethicaland

practicable,adouble-blinddesignisused,employingeithera

placebocontrolorastandardreferencedrugtherapyascontrol.Thesearethefirststudiesinthetargetpopulation,andit

ispossiblethatdrugeffects,includingadversedrugreactions

andpharmacokinetics,maybedifferenttothoseobservedin

thehealthysubjects.IftheexploratoryphaseIIstudiesare

promising,largerphaseIIIstudiesareinstigated,usinga

dosageregimendefinedonthebasisofthephaseIIstudies.ClinicalTrialPhasesPhaseIItrials:20-300patientsDoestreatmentdowhatitissupposedto?Howdoestreatmentaffectthebody?OncetheinitialsafetyofthestudydrughasbeenconfirmedinPhaseItrials,PhaseIItrialsareperformedonlargergroupsandaredesignedtoassesshowwellthedrugworks,aswellastocontinuePhaseIsafetyassessmentsinalargergroupofvolunteersandpatients.PhaseIIStudyPhaseIIstudiesaresometimesdividedintoPhaseIIAandPhaseIIB.PhaseIIAisspecificallydesignedtoassessdosingrequirements(howmuchdrugshouldbegiven),whereasPhaseIIBisspecificallydesignedtostudyefficacy(howwellthedrugworksattheprescribeddoses)

PreclinicalstudyofnewdrugPHASEII

PreclinicalstudyofnewdrugPHASEIIIPhaseIIIisthephaseoflarge-scaleformalclinicaltrialsinwhichtheefficacyandtolerabilityofthenewdrugisestablished.Patientgroupswhorespondmoreorlesswellmaybeidentified,patientexposure(bothnumbersanddurationoftherapy)

isincreased,andlesscommontypeB(seeChapter12)adverse

reactionsmaybeidentified.Duringthisperiod,themanufacturerswillbesettingupplantforlarge-scalemanufactureand

undertakingfurtherpharmaceuticalstudiesondrugformulation,bioavailabilityandstability.Themedicaladviserstothe

company,inassociationwiththeirpharmacological,pharmaceuticalandlegalcolleagues,willbegintocollatethelarge

amountofdatanecessarytomakeformalapplicationtothe

MHRAorEMEAforaproductlicence.

PreclinicalstudyofnewdrugPHASEIIIMarketingapproval

maybegeneralorgrantedsubjecttocertainlimitationswhich

mayincluderestrictiontohospitalpracticeonly,restrictionin

indicationsforuse,orarequirementtomonitorsomeparticular

actionororganfunctioninaspecifiednumberofpatients.

Doctorsarereminded(bymeansofablacktrianglesymbol

besideitsentryintheBritishNationalFormulary)thatthisis

arecentlyintroduceddrug,andthatanysuspectedadverse

reactionshouldbereportedtotheMHRAorCommissionon

HumanMedicines.ClinicalTrialPhasesPhaseIIItrials:From300tothousandsofpeopleIsthenewagentorintervention(ornewuseofatreatment)betterthanthestandard?Participantshaveanequalchancetobeassignedtooneoftwoormoregroups

PreclinicalstudyofnewdrugPHASEIII

PreclinicalstudyofnewdrugPHASEIVPhaseIVstudiesareprospectivetrialsperformedaftermarketingapproval(thegrantingofaproductlicence).Thesemayassessthedrug’sclinicaleffectivenessinawiderpopulationandmayalsohelpinthedetectionofpreviouslyunrecognizedadverseevents.ClinicalTrialPhasesPhaseIV:FromhundredstothousandsofpeopleUsuallytakesplaceafterdrugisapprovedUsedtofurtherevaluatelong-termsafetyandeffectivenessofnewtreatment

PreclinicalstudyofnewdrugPHASEIVPhasesofclinicalstudiesPhasePopulationNo.involvedperprotocolCommentsIhealthy20-80FirstinhumanspharmacokineticsIIpatients20-300Assessefficacy,optimaldoses,firstindicationsofsafetyIIIpatients300-severalthousandEfficacyandsafetycomparisonagainststandard,pivotaldataregistrationIVpatientsVariableLongtermefficacyandsafety,assessmentofrareadverseeventsPatientswhoagreetoentersuchastudymustberandomized

sothatthereisanequallikelihoodofreceivingtreatmentAorB.

Iftreatmentisnottrulyrandomized,thenbiaswilloccur.For

example,theinvestigatormightconsidertreatmentBtobe

lesswelltoleratedandthusdecidetotreatparticularlyfrail

patientswithtreatmentA.Multicentrestudiesareoftennecessaryinordertorecruitadequatenumbersofpatients,anditis

essentialtoensurethatthetreatmentsarefairlycompared.Designprinciplesforclinicaltrialofnewdrug

RANDOMIZATIONIf

treatmentAisconfinedtoonecentre/hospitalandtreatment

Btoanother,manyfactorsmayaffecttheoutcomeofthe

studyduetodifferencesbetweenthecentres,suchasintervalbetweendiagnosisandtreatment,individualdifferencesindeterminingentrycriteria,facilitiesfortreatmentofcomplications,differingattitudetopaincontrol,easeoftransport,etc.Designprinciplesforclinicaltrialofnewdrug

RANDOMIZATIONDesignprinciplesforclinicaltrialofnewdrug

RANDOMIZATIONRandomization1).Simplerandomization

2).Stratificationrandomization3).

BlockrandomizationBlindnessBlindnessinatrialmeansthatindividuals(investigatororparticipant)doesnotknowwhattreatmentisbeinggiven.Blindingtheinvestigatoristoeliminatethebias,whileblindingthepatientsistoeliminatethedifferencesinresponsesthatcanoccurbecauseofdifferencesinthepatient’sexpectationofwhataparticulartreatment,ornotreatment,maydo.SingleBlinded:ParticipantsdonotknowifinexperimentalorcontrolgroupDoubleBlinded:ParticipantsANDInvestigatorsdonotknowgroupassignmentTripleblinded:A&B,AorBControlorExperimentalgroup.Doubleblindanddoubledummy:A+b,B+a.IA‘double-blind’designisoftendesirabletoeliminatepsychologicalfactorssuchasenthusiasmforthe‘new’remedy.This

isnotalwayspossible.Forexample,ifinthecomparisonof

treatmentAandtreatmentBdescribedabove,treatmentA

consistsofregularintravenousinfusionswhilsttreatmentB

consistsoforalmedication,the‘blind’isbroken.As‘survival’

durationis‘hard’objectivedata,thisshouldnotbeinfluenced

markedly,whereassofterend-points,suchasthestateofwellbeing,aremoreeasilyconfounded.Designprinciplesforclinicaltrialofnewdrugnewdrug

DOUBLE-BLINDDESIGNIntrialswheretheseare

especiallyimportant,itmaybeappropriatetousemoreelaboratestrategiestopermitblinding,suchastheuseofa‘double

dummy’wherethereisaplaceboforbothdosageforms.In

thiscasepatientsarerandomizedtoactivetabletsplusplacebo

infusionortoactiveinfusionplusplacebotablets.Designprinciplesforclinicaltrialofnewdrug

DOUBLE-BLINDDESIGNPlaceboPlacebo:faketreatmentwithouttherapeuticvalue.Placebosareusedinordertoachieveblindness.Itisthereforeimportantthatplacebosbemadetomatchtheactivetreatmentascloselyaspossible.(samesize,shape,color,texture,weight,tasteandsmell)Ifaplacebocontrolisethicalandpractical,thissimplifies

interpretationoftrialdataandenablesefficacytobedeterminedmoreeasily(andwithmuchsmallernumbersofsubjects)thanifaneffectiveactivecomparatoriscurrentstandard

treatment(andhenceethicallyessential).Itiswellrecognized

thatplacebotreatmentcanhavemarkedeffects(e.g.lowering

ofbloodpressure).Thisispartlyduetopatientfamiliarization

withstudyprocedures,whoseeffectcanbeminimizedbya

placebo‘run-in’phaseDesignprinciplesforclinicaltrialofnewdrug

PLACEBOKnowndrugsaspositivecontrolorplaceboasnegativecontrol.Designprinciplesforclinicaltrialof

CONTROL&POSITIVECONTROL

StudyParticipantRecruitmentIdentifyeligibleparticipants(InclusionCriteria,ExclusionCriteria)ExplainstudyProvideinformedconsentReassesseligibilityAssigntoonegroupParticipantsshouldbetoldMayhavesideeffects(adverseeffects)TimecommitmentBenefits&risksMaywithdrawatanytimeEnrollment100%voluntaryParticipantsshouldbetoldMayhavesideeffects(adverseeffects)TimecommitmentBenefits&risksMaywithdrawatanytimeEnrollment100%voluntary

74BenefitsofParticipationPossiblebenefits:Patientswillreceive,ataminimum,thebeststandardtreatment(ifoneexists)Ifthenewtreatmentorinterventionisproventowork,patientsmaybeamongthefirsttobenefitPatientshaveachancetohelpothersandimprovepatientcare75RisksofParticipationPossiblerisks:Newtreatmentsorinterventionsunderstudyarenotalwaysbetterthan,orevenasgoodas,standardcareEvenifanewtreatmenthasbenefits,itmaynotworkforeverypatientMayhavesideeffects76PatientProtection Federalregulationsensurethatpeoplearetoldaboutthebenefits,risks,andpurposeofresearchbeforetheyagreetoparticipate77HowArePatients’RightsProtected?InformedconsentScientificreviewInstitutionalreviewboards(IRBs)Datasafetyandmonitoringboards(DSMBs)78InformedConsentAprocessinwhichapersonlearnskeyfactsaboutaclinicaltrial,includingpotentialrisksandbenefits,beforedecidingwhetherornottoparticipateinastudy.Informedconsentcontinuesthroughoutthetrial.Doctorswillgiveyouinformationaboutaparticulartreatmentortestinorderforyoutodecidewhetherornotyouwishtoundergosuchtreatmentortest.79ComponentsofInformedConsentPurposeProceduresPotentialrisksandbenefitsIndividualrights80Institutionalreviewboards(IRBs)Agroupofscientists,doctors