中英文-FDARegulatoryAffairs1

1、FDARegulatoryAffairs:AGuideforPrescriptionDrugs目錄1、藥品發(fā)展和FDA概述1、OverviewofDrugDevelopmentandtheFDADouglasJ.Pisano藥品發(fā)展和FDA概述1.1BriefHistoryofDrugLawsandRegulationsPriorto1902,theU.S.governmenttookahands-offapproachtotheregulationofdrugs.Manyofthedrugsavailablewereso-called“patentmedicineswhichweresona

2、medbecauseeachhadamoreorlessdescriptiveorpatentname.Nolaws,regulationsorstandardsexistedtoanynoticeableextenteventhoughtheUnitedStatesPharmacopeia(USP)becamearealityin1820asthefirstofficialcompendiumoftheU.S.TheUSPsetstandardsforstrengthandpuritythatcouldbeusedbyphysiciansandpharmacistswhoneededcent

3、ralizedguidelinestoextract,compound,andotherwiseutilizedrugcomponentsthatexistedatthetime.However,in1848,thefirstAmericandruglaw,theDrugImportationAct,wasenactedwhenAmericantroopsservinginMexicobecameseriouslyaffectedwhenadulteratedquinine,anantimalarialdrug,wasdiscovered.Thislawrequiredlaboratoryin

4、spection,detention,andevendestructionofdrugsthatdidnotmeetacceptablestandards.Later,in1902,theVirus,SerumandToxinsAct(BiologicsControlAct)waspassedinresponsetotetanusinfecteddiphtheriaantitoxinwhichwasmanufacturedbyasmalllaboratoryinSt.Louis,MO.Thirteenschoolchildrendiedasaresultofthetaintedserum.No

5、nationalstandardswereasyetinplaceforpurityorpotency.TheActauthorizedthePublicHealth1.1藥品法律和監(jiān)管歷史簡述在1902年之前，美國政府沒有對藥品進行監(jiān)管。當時市面上的絕大多數(shù)藥品都所謂的“專利藥物”，因為它們或多或少都是這樣宣傳的。即使美國藥典(USP)在1820年成為美國的第一份官方簡編，美國的法律法規(guī)或標準仍就一片空白。美國藥典為醫(yī)生和藥劑師提供了劑量和純度的標準。然而，1848年，第一個美國藥品法“藥品進口法”頒布。背景是當時正在墨西哥服役的美國軍隊遭受嚴重傳染，而此時抗瘧疾藥物奎寧被發(fā)現(xiàn)是摻假藥。這項

6、法律要求對實驗室進行檢查，拘留，甚至銷毀不符合法定標準的藥品。后來，在1902年，為響應(yīng)于由密蘇里州圣路易斯的小實驗室制造的用于破傷風感染的白喉抗毒素，通過了病毒，血清和毒素法(BiologicsControlAct)。背景是13名小學(xué)生由于接種受污染的血清而死亡。當時尚無針對血液制品的純度或效力的國家標準。此項法律授權(quán)公共衛(wèi)生服務(wù)部對用于預(yù)防或治療疾病的血清、疫苗和相關(guān)生物制品的州際銷售進行許可管理和監(jiān)督管理。Servicetolicenseandregulatetheinterstatesaleofsera,vaccines,andrelatedbiologicproductsusedto

7、preventortreatdisease.ThisActalsospurredDr.HarveyW.Wiley,chiefchemistfortheBureauofChemistry,abranchoftheU.S.DepartmentofAgriculture(USDA)andtheforerunnerfortodayU.S.FoodandDrugAdministration(FDA),toinvestigatethecountryfoodsanddrugs.HeestablishedtheHygienicTable,agroupofyoungmenwhovolunteeredtoserv

8、eashumanguineapigs,andwhowouldallowDr.Wileytofeedthemacontrolleddietlacedwithavarietyofpreservativesandartificialcolors.Morepopularlyknownasthe該法案還引發(fā)了時任美國農(nóng)業(yè)部（USDA）分支機構(gòu)化學(xué)局首席化學(xué)家HarveyW.Wiley博士的關(guān)注。FDA的前身就是美國農(nóng)業(yè)部（USDA）分支機構(gòu)化學(xué)局。他建立了衛(wèi)生研究計劃，招募了一群年輕男性志愿者，同意參加Wiley博士對防腐劑和人工色素的試驗研究。這就是后來著名的“毒藥隊”，是他們幫助了Wiley博士收集

9、了足夠的實驗數(shù)據(jù)，證明了美國的許多食品和藥物摻假，產(chǎn)品的劑量或純度是可疑的或與標簽不符，或產(chǎn)品標識信息不足或不準確。PoisonWiley博士后來寫了UptonSinclairsTheJungleSquad,“theyhelpedDr.WileygatherenoughdatatoprovethatmanyofAmericafoodsanddrugswereadulterated,theproductsstrengthorpuritywassuspectormisbranded,orproductshadinadequateorinaccuratelabeling.Dr.Wileyeffort

10、s,alongwithpublicationofUptonSinclairThesJungle(abookrevealingtheputridconditionsinAmericameatindustry),wererewardedwhenCongresspassedAmericasfirstfodruglawin1906,thePureFoodandDrugAct(USPFDA,alsoknownastheWileyAct).TheWileyActprohibitedinterstatecommerceofmisbrandedfoodsordrugsbasedontheirlabeling.

11、Itdidnotaffectunsafedrugsinthatitslegalauthoritywouldcometobearonlywhenaproductingredientswerefalselylabeled.Evenintentionallyfalsetherapeuticclaimswerenotprohibited.Thisbegantochangein1911withtheenactmentoftheSherleyAmendmentwhichintendedtoprohibitthelabelingofmedicationswithfalsetherapeuticclaimst

12、hatwereintendedtodefraudthepurchaser.Theseamendments,however,requiredthegovernmenttofindproofofintentionallabelingfraud.Later,in1937,asentineleventoccurredthatchangedtheentireregulatorypicture.Sulfabecamethemiracledrugofthe（一本揭示美國肉業(yè)骯臟條件的書）。1906年在國會通過美國第一個食品和藥物法，純凈，食品和藥物法案（USPFDA稱為WileyAct）上，Wiley博士被

13、嘉獎。Wiley法案禁止不符合標識信息的錯誤標簽食品或藥物在州際間貿(mào)易銷售。它不影響不安全的藥物，因為其法律權(quán)威只有在產(chǎn)品的成分被錯誤地貼上標簽時才會發(fā)生。即使故意的虛假治療信息也沒有被禁止。odand這在1911年隨著“謝利修正案”的頒布而開始改變，該修訂旨在禁止不符合用藥標識信息的虛假治療信息，而達到欺騙購買者的目的。然而，修正案要求政府找到有意標簽欺詐的證據(jù)。后來，在1937年，發(fā)生了一個警示事件，徹底顛覆了美國藥品監(jiān)管。磺胺類藥成為當時的奇跡藥物，被用于治療許多危及生命的感染。但它口感不好，難吞咽，這導(dǎo)致制藥者需要去尋求一個解決方案。timeandwasusedtotreatmanyl

14、ife-threateninginfections.Ittastedbadandwashardtoswallowwhichledentrepreneurstoseekapalatablesolution.S.E.MassingillCo.ofBristol,TN,developedwhatthecompanythoughtwasapalatable,raspberryfavoredliquidproduct.However,theyuseddiethyleneglycoltosolubilizethesulfa.Avolumeof6galofthisdangerousmixture,Elixi

15、rofSulfanilamide,killed107people,mostlychildren.TheresultwasthepassageofoneofthemostcomprehensivestatutesinthehistoryofAmericanhealthlaw.TheFederalFood,Drug,andCosmeticActof1938(FDCA)repealedtheSherleyAmendmentsandrequiredthatallnewdrugsbetestedbytheirmanufacturersforsafetyandthatthosetestsbesubmitt

16、edtothegovernmentformarketingapprovalviatheNewDrugApplication.TheFDCAalsomandatedthatdrugsbelabeledwithadequatedirectionsiftheywereshowntohavehadharmfuleffects.Inaddition,theFDCAauthorizedtheFDAtoconductunannouncedinspectionsofdrugmanufacturingfacilities.Thoughamendedmanytimessince1938,theFDCAisstil

17、lthebroadfoundationforstatutoryauthorityfortheFDAasitexiststoday.However,anewcrisisloomed.Throughoutthelate1950s,EuropeanandCanadianphysiciansbegantoencounteranumberofinfantsbornwithacuriousbirthdefectcalledphocomelia,adefectthatresultedinlimbsresemblingflipperssimilartothosefoundonseals.Thesebirthd

18、efectsweretracedbacktomotherswhohadbeenprescribedthedrugthalidomideinanefforttorelievemorningsicknesswhilepregnant.TheanufacturerofthisdrugappliedforU.S.S.E.MassingillCo.,Bristol,TN,開發(fā)了該公司認為是一種樹莓味的爽口液體產(chǎn)品。然而，他們使用二甘酉I溶解磺胺。6加侖的這種危險混合物磺胺藥，殺死107人，大多還是兒童。結(jié)果是通過了美國健康法歷史上最全面的法規(guī)。1938年的聯(lián)邦食品，藥品和化妝品法案（FDCA）宣布廢除了

19、Sherley修正案,并要求所有新藥要由其制造商進行安全性測試，并且這些測試應(yīng)通過新藥申請?zhí)峤徽M行市場批準。FDCA規(guī)定，如果藥物被證明具有有害作用，那么藥物必須貼上相應(yīng)標識標簽。此外，F(xiàn)DCA授權(quán)FDA對藥品生產(chǎn)設(shè)施進行突擊檢查。雖然自1938年以來修訂了很多次，但FDCA仍然是FDA今天廣泛存在的法定權(quán)威的基礎(chǔ)。然而，一個新的危機露頭了。在整個20世紀50年代后期，歐洲和加拿大醫(yī)生開始遇到一些嬰兒出生時出現(xiàn)一個奇怪的出生缺陷稱為phocomelia,這是一個缺陷導(dǎo)致四肢類似于海豹的鰭狀物。這些出生缺陷最終被追marketingapprovalofthedrugasasleepaid.H

20、owever,duetotheeffortsofDr.FrancesO.Kelsey,FDAschiefmedicalofficeratthetime,thecasewasmadethatthedrugwasnotsafe,溯到用于緩解孕婦妊娠病的藥物沙利度胺。這種藥物的制造商以睡眠輔助作用向美國申請。然而，時任FDA的首席醫(yī)學(xué)官FrancesO.Kelsey博士認為，該藥物不安全，因此阻止了其在美國上市。andthereforenoteffectiveforreleasetotheU.S.marketplace.Dr.KelseyeffortsanddecisiveworkbytheU.S.

21、CongressresultedinyetanothernecessaryamendmenttotheFDCAin1962,theKefauver-HarrisAct.ThisactessentiallyclosedmanyoftheloopholesregardingdrugsafetyinAmericanlaw.Itsdrugefficacyamendmentsnowrequireddrugmanufacturerstoprovesafetyandefficacyoftheirdrugproducts,registerwiththeFDA,andbeinspectedatleastever

22、y2years,havetheirprescriptiondrugadvertisingapprovedbytheFDA(thisauthoritybeingtransferredfromtheFederalTradeCommission),andprovideandobtaindocumentedainformedconsent”toresearchsubjectspriortohumantrials.Anincreaseincontrolsovermanufacturingandtestingwasaddedtodeterminedrugeffectiveness.Inaneffortto

23、addressthesenewprovisionsoftheact,theFDAcontractedtheNationalAcademyofSciences,alongwiththeNationalResearchCouncil,toexaminesome3,400drugproductsapprovedbetween1938and1962basedonsafetyalone.CalledtheDrugEfficacyStudyImplementationReviewof1966(DESI),itchargedtheseorganizationstomakeadeterminationasto

24、whetherpost-1938drugproductswere“effective“fortheindicationsclaimedinth在Kelsey博士和美國國會推動下，1962年通過了對FDCA的另一個必要修正，即Kefauver-Harris法案”。這一法案基本上完善了美國法律中關(guān)于藥物安全的許多方面。修訂案在藥物功效方面要求藥品制造商證明其藥品的安全性和有效性，向FDA注冊，并至少每2年接受檢查一次，由FDA批準其處方藥廣告（這樣權(quán)力現(xiàn)在已經(jīng)移交到聯(lián)邦貿(mào)易委員會），并在人體試驗前向研究對象提供并獲得記錄的“知情同意”。增加了對生產(chǎn)和檢測的控制，以確定藥物的有效性。為落實如上規(guī)定，

25、FDA已將與國家科學(xué)院，攜手國家研究理事會，對1938年和1962年之間批準上市的約3,400種藥品進行安全性審查。1966年的藥物功效研究實施審查（DESD,它要求相關(guān)組織對1938年批準上市之后的藥物進行有效性審查，分為“有效”，“可能有效”，“可能有效”“或”無效的如果不被認為是”有效“的產(chǎn)品，將采取撤市、重新配方或明確警告處方中的該產(chǎn)品不是有效i的而才可繼續(xù)銷售。labeling,“probablyeffective,“possiblyeffective,“oraineffective.Thoseproductsnotdeemed“effective“wereeitherremoved

26、fromthemarketplace,reformulated,orsoldwithaclearwarningtoprescribersthattheproductwasnotdeemedeffective.Later,in1972,theFDAbegantoexamineover-the-counter(OTC)drugproducts.PhaseIIoftheDrugEfficacyAmendmentsrequiredtheFDAtodeterminetheefficacyofOTCdrugproducts.Thisprojectwasmuchlargerinscopethantheana

27、lysisofprescriptiondrugs.The1970sAmericanconsumercouldchoosefrommorethan300,000OTCdrugproducts.TheFDAsoon然后，在1972年，F(xiàn)DA開始對（OTQ藥品進行審查。修訂案要求FDA需要確定OTC藥品的有效性。這項計劃要比分析處方藥更加艱巨復(fù)雜。20世紀70年代美國消費者可以選擇超過30萬的非處方藥物產(chǎn)品。FDA很快意識到，它沒有資源來評估每一個。因此，建立了由科學(xué)家、醫(yī)療專業(yè)人員和消費者的咨詢小組，負責評估在80種已確定的治療類別的在OTC產(chǎn)品中使用的活性成分。在審查科學(xué)和醫(yī)學(xué)文獻后，咨詢小組就

28、活性成分及其標簽做出了決定。結(jié)果是確定了一個專論，詳細描述了在一個治療等級下可接受的活性成分和標簽。符合專論指導(dǎo)原則的產(chǎn)品被認為是“第一類：安全有效，沒有誤導(dǎo)”。然而，不符合專論指南的產(chǎn)品被認為是“第二類：不安全和有效或錯誤標記。第二類產(chǎn)品從市場或再造。數(shù)據(jù)不足以分類的產(chǎn)品被認為是III類，并允許繼續(xù)在市場上銷售直到可以建立實質(zhì)數(shù)據(jù)或直到它們再造后并符合專論。OTC藥物審查花了近20年才完成。盡管在整個70年代通過了許多聯(lián)邦法律和法規(guī)，但大部分是基于規(guī)范醫(yī)療專業(yè)人員的做法或直接保護消費者。例如，1970年“綜合藥物濫用和預(yù)防法案”其中的“聯(lián)邦控制物質(zhì)法”（CSA）規(guī)定，將具有相對較高濫用可能性

29、的藥物指定存放在五個聯(lián)邦地區(qū)，并通過一個授權(quán)的的記錄保存系統(tǒng)，用于跟蹤濫用藥物通過特定紙張進行采購、處方、分發(fā)和使用的全過程。realizedthatitdidnothavetheresourcestoevaluateeachandeveryone.Hence,itcreatedadvisorypanelsofscientists,medicalprofessionals,andconsumerswhowerechargedwithevaluatingactiveingredientsusedinOTCproductswithin80definedtherapeuticcategories.A

30、fterexaminingboththescientificandmedicalliteratureoftheday,theadvisorypanelsmadedecisionsregardingactiveingredientsandtheirlabeling.Theresultwasamonographthatdescribedindetailacceptableactiveingredientsandlabelingforproductswithinatherapeuticclass.Productsthatcompliedwithmonographguidelinesweredeeme

31、d“Category:SafeandEffective,NotMisbranded.However,productsnotincompliancewithmonographguidelinesweredeemed“CategoryII:NotSafeandEffectiveorMisbranded.CategoryIIproductswereremovedfromthemarketplaceorreformulated.ProductsforwhichdatawasinsufficientforclassificationweredeemedCategoryIIIandwereallowedt

32、ocontinueonthemarketuntilsubstantivedatacouldbeestablishedoruntiltheywerereformulatedandincompliancewiththemonograph.TheOTCDrugReviewtookapproximately20yearstocomplete.80年代也發(fā)生了重大的監(jiān)管變化。當時生物制藥行業(yè)處于領(lǐng)先地位。許多藥物化合Thoughtherewerenumerousotherfederallawsandregulationsthatwerepassedthroughoutthe1970s,manywereb

33、asedonregulatingthepracticeofmedicalprofessionalsorwereforthedirectprotectionofconsumers.Forexample,TheFederalControlledSubstancesAct(CSA),partoftheComprehensiveDrugAbuseandPreventionActof1970,placeddrugswitharelativelyhighpotentialforabuseintofivefederalschedulesalongwithaclosedrecord-keepingsystem

34、designedtotrackfederallycontrolledsubstancesviaadefinitepapertrailastheywereordered,prescribed,dispensedandutilizedthroughoutthehealthcaresystem.The1980salsopassedwithsignificantregulatorychange.Biotechnologyhadbegunonagrandscaleandthepharmaceuticalindustrywasonitscuttingedge.Manyofthemedicinalcompo

35、undsbeingdiscoveredwereshowntobeveryexpensiveandhavelimiteduseinthegeneralU.S.population.However,thesecompoundscouldprovelifesavingtodemographicallysmallpatientpopulationswhosufferedfromdiseasesandconditionsthatwereconsideredrare.Inanefforttoencouragethesebiotechpharmaceuticalcompaniestocontinuetode

36、veloptheseandotherproducts,CongresspassedtheOrphanDrugActin1983.TheActcontinuestoallowmanufacturerstogainincentivesforresearch,developmentandmarketingofdrugproductsusedtotreatrarediseasesorconditionsthatwouldotherwisebeunprofitableviaasystemofbreaksanddeductionsinamanufacturercorporatetaxes.Thoughth

37、esuccessoftheOrphanDrugActprovidedgreatmedicalbenefitforafew,ascandalwasloominginotherpartsofthepharmaceuticalindustry.Thegenericpharmaceuticalindustryexperiencedsteadygrowthasmanyoftheexclusivepatentsenjoyedbymajorpharmaceuticalcompaniesforbrand-namedproductswerebeginningtoexpire.Genericversionsoft

38、hesenowfreelycopiedproductswereappearingmuchmorefrequentlyinthemarketplace.However,thesegenericcopieswererequiredtoundergothesamerigoroustestingthatbrand-name,pioneerorinnovatorproductsdid.Thisledtoaverypublicscandalinwhichafewunscrupulousgenericpharmaceuticalcompaniestookshortcutsinreportingdata,su

39、bmittedfraudulentsamplesandofferedbribestoFDAofficialstogaineasyandrapidmarketapprovaloftheirproducts.Asaresult,CongresspassedthePriceCompetitionandPatentRestorationActof1984.ThisAct,alsocalledtheWaxman-HatchActafteritssponsors,wasdesignedtoleveltheplaying物的發(fā)現(xiàn)是極其昂貴的，并且在美國大眾人群中使用有限。然而，這些化合物被證明對被認為患有罕

40、見疾病和病癥的少數(shù)群體，能從統(tǒng)計意義上提高生命。為了鼓勵這些生物技術(shù)制藥公司繼續(xù)開發(fā)這些和其他產(chǎn)品，國會于1983年通過了“孤兒藥物法”。該法從公司稅上支持制造商繼續(xù)對罕見疾病的藥物產(chǎn)品的研究開發(fā)。盡管“孤兒藥物法”成功的為少數(shù)人提供了巨大的醫(yī)療好處，但是在制藥行業(yè)的其他部門卻出現(xiàn)了丑聞。s仿制藥行業(yè)經(jīng)歷了穩(wěn)步增長，因為主要制藥公司對于品牌產(chǎn)品享有的許多獨家專利開始過期。然而，仿制藥被要求應(yīng)與原研藥接受樣的嚴格檢測。這導(dǎo)致了一個非常公開的丑聞，其中一些不道德的仿制藥公司修改報告數(shù)據(jù)，提交虛假樣本，并向FDA官員提供賄賂，以獲得其產(chǎn)品的簡單快速的市場批準。因此，國會通過了1984年的價格競爭和專

41、利恢復(fù)法案。該法案也被稱為“Waxman-Hatch法案”，旨在平衡處方藥行業(yè)市場環(huán)境，包括原研藥與仿制藥。fieldintheprescriptiondrugindustrywithregardtopioneer/innovator/brandnameprescriptiondrugproductsandtheirgenericcopies.TheActwascomposedoftwodistinctpartsor“titles.TitleIwasforthebenefitofthegenericpharmaceuticalindustry.ItextendedthescopeoftheAb

42、breviatedNewDrugApplicationtocovergenericversionsofpost-1962approveddrugproducts.Itrequiredthatgenericversionsofpioneerorinnovatordrugshavethesamerelevantaspectsasthosewithregardtobioequivalence(rateandextentofabsorptionoftheactivedruginthehumanbody)andpharmaceuticalequivalence(samedosageformasthepi

43、oneerdrugtowhichitiscompared).Thoughsomewhatsimplified,theWaxman-HatchActpermittedeasiermarketaccesstogenericcopiesofpioneerdrugsprovidedtheywerenotsignificantlydifferentfromthepioneerdrugintheirabsorption,action,anddosageform.Inaddition,TitleIIoftheActwasdesignedtoaidandencourageresearchbasedoninno

44、vatorpharmaceuticalcompaniesincontinuingtheirsearchfornewandusefulmedicinalcompoundsbyextendingthepatentlifeofpioneerdrugproductswhileintheFDAreviewperiod.However,thepatentextensionbenefithasbecomesomewhatmootduetoanoverallreductioninFDAreviewtimeasaresultofprescriptiondruguserfees.In1992,Congresspa

45、ssedthePrescriptionDrugUserFeeAct(PDUFA).TheActwasintendedtohelpFDAgenerateadditionalfundstoupgradeandmodernizeitsoperationsandtoacceleratedrugapproval.ItauthorizedFDAtochargepharmaceuticalmanufacturersa“useracceleratedrugreview.AsaresultofthePDUFAlegislation,FDAhasbeenabletoreduceapprovaltimeofnewp

46、harmaceuticalproductsfromgreaterthan30monthstoapproximately13to15monthstoday.However,theActhada“sunsetprovlimitedFDAauthoritytochargeuserfeesuntil該法案由兩個不向的部分或“標題”組成。標題I是為了仿制藥行業(yè)的利益。它將“簡化新藥申請”的范圍擴大到涵蓋1962年后批準的不受商標保護的藥品。它要求應(yīng)與原研藥具有生物等效性和藥學(xué)一致性（相同劑型）。雖然有些簡化，但是Waxman-Hatch法允許更容易的市場準入，對于那些在吸收、用途和劑型一致的沒有重大變化的仿制藥。標題II旨在幫助和鼓勵基于創(chuàng)