中美仿制藥研發(fā)和申報流程涂家生，Ph.D.中國藥科大學藥劑學教授Tel:025-832713052011.11鄭州我國仿制藥申報、審評和研發(fā)對策主要內(nèi)容中美關(guān)于原研藥和仿制藥的背景美國仿制藥：申報、基于問題的審評和研發(fā)對策展望1234藥物經(jīng)濟學催生美國仿制藥制度美國社會安全制度導致政府赤字嚴重SSA已經(jīng)破產(chǎn)：如何破局？降低醫(yī)療費用成為必然Hatch-Waxman法案出臺美國FDA藥品注冊申請：新藥（兩類）、仿制藥和非處方藥申請1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)NDA的研發(fā)和申報505(b)(1)新藥申報資料內(nèi)容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology6.

HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification505(b)(2):歷史過程HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition(2003)可以降低研發(fā)的費用和審評力量的浪費505(b)(2)的關(guān)鍵:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的意義介于全創(chuàng)新藥物和仿制藥之間具有專利保護，且不存在產(chǎn)權(quán)糾紛和仿制藥不同，無替換的要求

應(yīng)有突破505(b)(2)范圍NewChemicalEntity(rarely)：我國Newdosageform：我國5類Newdosingregimen：我國補充申請Newstrength：我國補充申請Newrouteofadministration：我國2類Newindication：我國1.6505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“Genericbiologics”505(b)(2)排他性Exclusivitiesavailablefor505(b)(2)productsNCEExclusivity(5years)NewProductExclusivity(3years)OrphanDrugExclusivity(7years)Pediatricexclusivityextensions(6months)PatentIssues505(b)(2)drugscanhaveOrangeBook-listedpatents,andenjoy30-monthstayprotectionagainstgenericcompetitorsBut,505(b)(2)NDAsmayalsobeblockedbypatentsonReferenceDrugs505(b)(2)新藥的成功例子NCEThalomid?(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(b)(2)新藥的例子NewDosingRegimenTramadolextendedreleasetablets(2005)NewStrength/FormulationAntara(micronizedfenofibratecaps)(2004)(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)(2005)Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)505(b)(2)新藥的例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)505(b)(2)新藥的例子“GenericBiologics”O(jiān)mnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*ExamplesbasedonpubliclyavailableinformationFDANDA審評過程FDA可以使用已有數(shù)據(jù)用于審評NDA嗎？Hatch-Waxman之前,國會限制FDA在審評NDAX時應(yīng)用NDAY的數(shù)據(jù)：“NodatainanNDAcanbeutilizedtosupportanotherNDAwithoutexpresspermissionoftheoriginalNDAholder.”[FDA“FinkelMemorandum”(1978,1981)]Hatch-Waxman解除只適合ANDAs：ANDAprocessallows“genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant....”505(b)(2)doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires“fullreportsofinvestigations”establishingsafetyandeffectiveness[21USC§§355(b)(1)(A),(d)(1)]美國仿制粘藥Ag繞ene遙ric返dr果ug列pro田duc油ti關(guān)so靜ne磨tha期ti餅sc戶omp丙ara道ble耍to娃an零in熟nov薦ato嫩rd具rug茫pr蝕odu敢ct各(a抓lso妖kn需own撲as加th獻er蒸efe腰ren景ce稠lis爛ted掛dr魯ug賞(RL辱D)般pro裳duc損ta跟si盆den圣tif歉ied姨in色th榴eF刊DA’險sl奏ist僻ofAppr羞oved烤Dru右gPr灣oduc桌tsw掩ith墊Ther疊apeu典tic盆Equi逆vale包nce瞧Eval沖uati播ons)in獎dos牽age改form互,st顛reng蜻th,巧rout索eof暑adm妙inis爹trat深ion,題qua扛lity敏,pe摟rfor默manc壺ech排arac噴teri引stic肆san越din運tend嫂edu彩se.Gen撲eri翼cd趴rug賀ap下pli優(yōu)cat壇ion國sa倘re攏ter牙m(xù)ed虜“a燃bbr豬evi扒ate的d”壞in紀tha萌tt獎hey慰ar埋eg坐ene信ral緊ly珍not要re烏qui悠red鋸to出in刻clu制de竭pre泳cli損nic別al趁(an泊ima拿l)梢and俊cl圣ini賤cal酸(h采uma探n)衣dat朵at貿(mào)oe蘋sta風bli擔sh爛saf防ety橫an劍de架ffe各cti抹ven磨ess長.The岡se英par杯ame友ter按sw庫ere牽es桃tab旬lis卷hed缸up插on濾the塌ap虹pro暫val語of衛(wèi)th鏟ei憂nno岸vat瓦or觀dru敬gp選rod范uct疾,w券hic位hi方st牙he艙fir上st及ver牢sio飾no溜ft驚he翼dru仇gp見rod容uct脅ap綠pro抱ved艘by若th巡壽eF最DA.FDA審評仿碌制藥程譜序二、美國秒仿制藥的浪申報、審猴評和研發(fā)豎對策由FDA的OGD審評審評方式攝采用QbR申報資料沿采用CTD資料內(nèi)容倡也針對問盛題Off毯ice顫of云Ge返ner腿ic屑Dru扯gs如何保五證審評缸質(zhì)量和秩效率？Stru夢ctur干edP素rodu雷ctL掌abel聾ing擾(SPL束)Make相sla昂beli降nga羽vail松able牛on撥Inte從rnet尖via搭Nat退iona幸lLi欄brar耐yof罵Med捉icin廟e(N亡LM)Rev壘iew醫(yī)Ef臂fic鴨ien劍cie督sEar梅ly耍DMF欺re佛vie摘wClus傷ter鳥revi茅ews濾–pr碑oduc呼tsp敞ecia擇list扭sSup脂ple臘men自tt菌ria陳gin蚊ga牽tt詞eam卷le在ade震rl刷eve揮lDBE教Trun嫂cate在dRe懲viewQue塵sti隊on術(shù)bas甚ed幕Rev墊iew未(Q仆bR)Wil吊lh逼ave拆a著ver通yp閉osi鬼tiv優(yōu)ei累mpa野ctNew予re愿sou蛋rce狂sd委eve媽lop浮edDis削sol永uti綢on擺Dat笨aba產(chǎn)seIndi棉vidu雕alP咐rodu濫ctB棕ioeq吐uiva除lenc黃eIn娃form情atio姨nEnc棉our費age娛dt番he張use宋of良te主lep男hon俯ei竿nr搶evi村ew雕pro附ces片sIncr臺ease弄dth抬enu舍mber獲of墾1stcycl門eap伯prov朗alsDecr抗ease廣dth岡eto我tal佳numb畫ero楊fre舊view嘴cyc沒lesTota視lti戶met漫oap尤prov假ald冬idn怪oti惠ncre漢ase廈ins恥pite箏of星incr南ease盯dwo譯rklo折adDissolutionMethodsforDrugProductsNew!!benThis劑gui袋danc梁eco寺ntai炒nsa富nInt浩ern處et興lin供kto符al施ist鎮(zhèn)ing犯of朵dr對ug茫pro拘duc痕ts,ea很chl妨inke巾din雄tur管nto炮ac搬orre劈燕spon視ding壇bio聚equi趨vale厚nce鍵reco蹦mmen粉dati勁on.作Cli竄ckin屑gon讓ap樂rodu帳ctn笛ame往int應(yīng)hat紅list血wil慢lbr腿ing超upt辭hebio館equ回iva施len痛ce肚rec教omm乏end最ati尿ons蜻fo輛rt住hat啞sp終eci雄fic侍pr滴odu透ct.Reco各mmen遷dati鴨ons軌have忌bee捷nde案velo球ped扮for峰seve攏ral停drug撒sth賀ata壺ren屋oty貪ete前l(fā)igi哥ble開for物gene耽ric械comp賄etit辯ion表(i.e榴.,n鼓ewly呈app蹈rove怖dpr太oduc述ts)干and拜some緩old蠅erp憶rodu較cts象for間whic頁hin鐮form菊atio碗nha納spr樸evio鬧usly顯bee柄npr區(qū)ovid慘ed.淡Asadd童iti桃ona犬lr粱eco糕mme彩nda浮tio汪ns魚are個de需vel椅ope謀d,汽tho極se迷wil革lb攔ep漢ost拜ed寧on茶the犬We川bs帝ite.W鍋hen湖this頌gui露danc娛eis奧fin撕aliz順ed,械the緞list錦ing歸will逼be蝦avai刻labl慈eth薦roug煙hth灶eAg客ency鉗’sW逮ebp慶age.OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/2005Alosetron1mgTabletOral5/31/2005Atazanavir200mgCapsuleOral3/18/2005Atomoxetine60mgCapsuleOral6/13/2005CefditorenPivoxil200mgTabletOral3/18/2005Dutast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模塊2模塊2為概論。它包括藥理作用分類，作用模式以及臨床適應(yīng)證。模塊3應(yīng)該包含原料藥和制劑相關(guān)的化學、生產(chǎn)和質(zhì)量控制信息。FDA仿制藥部宗（OGD）鼓勵誓申請人壇根據(jù)ICH對于人用即藥物的注象冊技術(shù)要壩求，即通肝用技術(shù)文堂件（CTD）的格監(jiān)式，提絡(luò)交ADNA。包括劃以下模飼塊：模塊4模塊4是關(guān)于動物實驗的信息，并不是ANDA要求的。所以，仿制藥申請一般不包含模塊4。

模塊5模塊5是臨床研究報告。對于ADNA，生物等效性信息應(yīng)該在這個部分體現(xiàn)，包括：①生物等效性研究；②體外－體內(nèi)相關(guān)性研究；③生物分析方法開發(fā)。案例報告，包括不良反應(yīng)事件報告也應(yīng)包括在此。

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