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D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C ochrane G erm any , W iley O nline L ibrary on [14/01/2023]. S ee the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com DRUG SAFETY EVALUATION /doi/ by ibrahim ragab - C ochrane G erm any , W iley O nline L ibrary on [14/01/2023]. S ee the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from DRUG SAFETY EVALUATION https://onlinelibrary.w iley.com /doi/ by ibrahim Fourth Edition ragab - C ochrane G erm any , W SHAYNE COX GAD iley O Gad Consulting Services nline L DGEadX CToEnRsu Wlti.n Sg USLerLviIcVeAsN, JR. ibrary on [14/01/2023]. S ee the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from T©EJohd h2iisnt0i o2eWdn3i i tJHlieooyihsn nt& of iWr rSysiotl enpysu b(&1li esS,h o2en0ds0 ,2 3I0;n 22c3.e, 2009; 3e, 2017) https://onlinelibrary.w All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, iley.com maTRvheeagecii lhsraiatbgenlrhieect daao ltfO, hSpftfhthipcoa:eyt/o/nwceow Cpwyoi.xnw gGi,l earyde. ccaoonrmdd i/Dnggoe x/optree rro mWthie.s srSwiuoilnslsiev., aenx,c Jerp. tt oa sb ep eirdmenitttiefide db ya sl atwhe. Aaudtvhiocres oonf hthoiws wtoo orkb thaains bpeeermn iassssieornte tdo irne uascec omrdaatenrciael w friothm l athwi.s title is /doi/ by ibrahim ragab - C John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA ochrane G For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. erm Wiley also publishes its books in a variety of electronic formats and by print- on- demand. 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See the T and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect erm tmo etrhceh aancctaubrailcityy oorr cfoitmnepslse tfeonre as sp oarft tihcue lcaor nptuernptos soef. tNhios wwaorrrka natnyd m spayec bifei ccarlelayt eddis oclra eimxt eanldl ewda rbrya nstaileess, rinepclruedseinngta wtivitehso, uwt rliitmteinta staiolens amnya tiemripallsie odr wparorrmanottiieosn aolf s and C sirstsnhettharcfaaatootlet rlmewm mbgemeeiaben telssitino isactd nbeofa oslndet rilto oiaftesohintsnries se n da idow tni tnyhmo m ertlarkhoeye.isai ssTmnn w oh matfehok aaprefyktar. o ctTnmhftoh ietattih y spoba urwhte ba aaoslnvnuiryes kioh t coarieshgbtr haa lsaeennon rgilf zddocea odrawt m iuyooitotmrnhh u,od e rtwri hrsssceae iiet pbauunpsland iedttdoiaeaoerr,msr neosed.atr Ya tg bphnoeeredsuot ,iwi dnsniunhegfoecco tntlruh um ilawdsdta i rhntcteiheogofenne nb rsp turouhuetrli bdts ns l wowtieosrtiho vtliheriinkmcr a e tiwih sssti epatsndhse ow ectwt oi ooear rrnlsikigtpgst aeetaan ncsgwi i ezaaahda lnec, td iriiinote naw ncrat,iehip odnwepnednre ne oabitrnptasi drlnii,sti/ gea ocr ,torpe eo na.rp rodsFo fep.ut eqerNrsonutsehdteiiieounatrhnctl,i et aasr rlmole ,stau haoedryerrcev eroppis tcuro hoesbfehvs lfr.ioiu sdTduhreatlhe hdmoere rbnara e god erva swiac.uaetr haeon rds onditions (https://onlinelibrary.w Library of Congress Cataloging- in- Publication Data iley.com Names: Gad, Shayne C., 1948- author. | Sullivan, Dexter W., Jr. author. /term TD I d ieb9etlsi7nebc8t:rli 1iifDopi1egrt1riuros9ag:n7p L:s5h a4C5ifct8eCha5t lNye2 r d ee(2ivfct0eailo2orluen2thna.0 )tc|4i e|oH2 sIn5 oSa 2b/Bn 0oSdN kh( ip ean9nryd7i,nn e8Netx1) .J 1C| 1:Lo 9WxC7 CGi5l5eNay8d ,62, 290D0 2(e22ax3d0t.oe4 |rb2 IeW5n 2cp.1l dSu f(du)e elb|l siIo vSoaBkn)N J |r .ISBN s-and-conditions) on W S u9b7j8e1ct1s1: 9M75E5S8H7:6 D (erpuugb E)valuation, Preclinical | Drug Evaluation | Product iley O C LLC CCloSDav usDreesrebrviCcf oeDoi oci6rlekad1last 5irianoeg/vc.ncn1aeo::9i, rl LW—aPdCb oaidlCslveect a my2aRi3tla Aa/hrebk1tnlte2epgt 3si/an:28t/g 0 /h l2(ctp2tcprn1isn.1:l/t1o/)0cl c|. gcLnoC.vlC/o2c R0.g2Ao21v02/42320852 2 2(00eb4o2o5k2)1 | NLM QV 771 | nline Library for rules of use; O CSeotv ienr 1Im0/a1g2ep:t ©Ti VmIeCs TLOTR S tHd AbBy BSItrCaKiv eV, ICShIOenNnSai/,G Ientdtyia Images A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C ochrane G erm any , W iley O nline L ibrary on [14/01/2023]. S ee the T To my beloved Novie Betho,u fro rm yaetarorns oafn ldo vaelw aanyds sau pfipreocrrt,a acknedr .to my aunt Ernestine, who is erms and C To Adrienne and Aydewnh, ofo nr eyvoeurr f apialtsi eton cien sapnidre s mupep woirtth, ahnedr ctoo umrya gmeo.ther, Debby M—an Ddeevx—itlel Ser ,hW ay. nSeu lCliovxan G, aJrd. onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com ACKNOWLEDGMENT /doi/ by ibrahim ragab - C ochrane G erm any , W iley O nline L Katina Gad’s support and assistance were essential to the completion of this book. ibrary on [14/01/2023]. S ee the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C vii reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com CONTENTS /doi/ by ibrahim ragab - C ochrane G erm any , W iley O nline L PARBEOFUATC TEH E AUTHORS xxxxixxi ibrary on [14/01/2023]. S 1 The Drug Development Process and The Global Pharmaceutical ee the T erm M11111.....12345a rkeITHTSL1tn.pthhoi5trslreena.ato1 tgoMDced regGuyra iuc aerogtkmsDif oe DFeoMtnpo e Olro1v1a de2nDcleleoeyr vpn W1em Tloehhpnaemttr YaPeporneoutuc: MteLiscaussr s gt17 e1( TVheers Sush oSrmt Galal mCeo)m 1p3any or The Short Versu1s s and Conditions (https://onlinelibrary.w 1.5.2 Minimize the Risk of Subsequent Failure 13 iley.com 1.6 Safety Assessment And The Evolution Of Drug Safety 14 /term 2 1RRR.eeo7fgu eutreelasnT tTchieooesn TH o1huf7r meHeau Snmt aUagnsee sP aohnfa dDr mMruagac rSekuaefttei ctya lE Svaafleutayt:io n In The General Case 16 19 s-and-conditions) on W 2.1 Introduction 19 iley O 2.2 Brief History of Us Pharmaceutical Law 19 nline L 2222....2222....3421 11F119999D6930A2286R:,:: 1MFPA9ou a9or2je7do4 ,,Fr 2DoA0orm0ud2g ea,n, n 2dad0nm 0dDe7 Crn,u to2 gs02 Am132ce,tt iac1n 9Ad c2t0 1271: PDUFA, FDAMA, and ibrary for rules of use; O A 22..34 22FO2222......dv224422ae......78m1265rv ai eSwuECRRIP CmoRlOeeeHfggmEcV uuu:tAa rIllsIaaoDr :nyRtt nTtii-:eooie 1 chCrgnn9 neRuss o a::lP2ne taGHie7sctoeidoeunoqirnmanadueltsiea rrn Cinancg2lc o Ps8ReCn:hs feoE aeasnrrlenmeseadicndra tccOreceohret an uhoEtitenicqior c uH SnaRisulates ybr g2m mA2u8o8licasntts iiizo2oan7ntsiso In2m 82p7act 27 articles are governed by the applicable C ix reative C om m ons L icense D ow x COnTEnTS nloaded from 2222....4444....3564 RRRReeeegggguuuullllaaaattttiiiioooonnnnssss:: :V AEBeninrosvtliuiobrsogi oLnictmaiscw es3 n033ta10l Impact 30 https://onlinelibrary.w 22..56 OPrrogcaensisz aOtifo Pnhs aRrmegaucleautitnicga Dl Prurogd Aucntd D Deevveilcoep mSaefnett ya nInd TAhpep rUonviatle d3 2States 32 iley.com 2.7 T22..e77s..t12in g GTGuoeixdnieeclriiatnyle osT re 3Ss4tyinstge:m Tartaidci tTiooxniacli Ptyh Aarsmseascsemuteincta ls3 434 /doi/ by ibrahim 22..77..34 GSaefneetyti cP Thaorxmicaictyo lAosgsye s3sm6ent 34 ragab - C 22..77..65 RLoepcarol dTuiscstuivee T aonlde rDanecvee lo3p6mental 37 ochrane G erm 22..77..78 CToaxrcicinitoyg Teensictiintyg : 3B7iotechnology Products 37 any , W 2.8 Toxicity/Safety Testing: Cellular And Gene Therapy Products 39 iley O 2.8.1 Cellular Therapies 40 nline L 22222.....88888.....23456 GeiPBnxrae e vsnvciieilcvvi onToP i hrc4i4ean0r0lca Sippailefeess t yf4o 0Er vParleucaltiinoinc al4 1Safety Evaluation of Cellular and ibrary on [14/01/2023]. S 2.8.7 GAedndeit iTohnearla Cpioenss i4d1erations for Cellular Therapies 41 ee the Term 2.9 2T.o8x.8ic ity TAedsdtiintigo:n Sapl eCcoianls iCdaesreasti o4n1s for Gene Therapies 41 s and C 222222......999999......123456 OLVOOSpiarnpfaceectlcic-o cii TClnaaohlloeg rsnIPeys toao r4Dpatm2ecurneeulaiprgnsttsig io v 4anDen3ssid: s Pe4Iam2esdaeigsa it(nrCigco Aamngpdea nGstssei or4ina3atrtiec UCslea)i m4s2 43 onditions (https://onlinelibrary.w 2.10 2222I2n.....99991te....07918r.n 0 1a tioOEIBTInnnyxoratppDpetla ehreP)nnsad h aini4ocatt 5ieafDro dlmn nr Duaaaengrclw udesC g u DAo 4tPiuru5curngaogclmd iARlue cfpenotgptsreul idHlc4a aR5attirioomounnot saen ns(i dzntoa DRt AiAeopgnspi )sr 4tor48av8tailo (nO 4n8ce you have an iley.com/terms-and-conditions) on W 2.10.2 Other International Considerations 52 iley O 2.10.3 Safety Pharmacology 58 nline L 2.11 C222...o111m111...b231i naDACStiuooedbnvomm irPcidnierisoin ssPdaitroteuoirncog stnrs5 a 95m55998s That Are CDER and CBRH Each Will ibrary for rules of use; O A 22RF..ue11rf23teh reernMC cRoeeenesac tdil6nui4ngsigso An6 n66d4 Submissions To Fda Toxicologists 63 articles are governed by the applicable C reative C om m ons L icense D ow COnTEnTS xi nloaded from 3 DI3n.a1 St at uMdI3ny.i1nt rA.io1nnd gud:c PStCiorolounagr imrc6ae7ssm o6 Df7 Iensfigonrm aantdio Inn FSoarfe Ctyo nEsviadleuraattiioonn 67 https://onlinelibrary.w 33..11..32 TPrimioer Kanndo wEcleodngoem 6ie7s 67 iley.com 333...111...456 MSMeioasnrcciethlo lrPainrnoegco ePudusu bRrleies fhe7er0edn Lciet eSroauturrcee sa n6d8 Other Research in Progress 70 /doi/ by ibrahim 3333....1111....7891 0 KTMCoaianxntdieacsrd i Rioaalfen lSI eCnaaffesoenert tymIr neDav tfeaioontrant Oo Sr7chy1ce (ueTptsRa t(IiM)o nS7aD1l HS)e a7lt1h and Safety (CCInFO) 72 ragab - Cochrane Germ 33..11..1112 PMoeldlulitnioen 7a2nd Toxicology (POLTOX) 72 any , W 3.2 Pc- Based Information Products: Laser Disc 72 iley O 3.2.1 International Veterinary Pathology Slide Bank (Ivpsb) 72 nline L 4 E3RF.ule3erf ctehtrreeornC ncRoeiencsac Rdl7uie3nscigoo rn7d 4s7,3 Reporting, and Submission: eCTD and Send 75 ibrary on [14/01/2023]. S 4.1 Introduction 75 ee the T 4.2 Submission of Send Data In Module 4 of The eCTD 76 erm 4.3 Send Background 76 s and C 4444....4567 SSSDA444...eeees777nnn t...Seddd123re mRFSnetdeiuang dFTSFtauuyyDtitlulri apeoeSAdtessnouy Corb o87ySfmef07 t AnaSi7tsrpt7etsu priDd olii8nace0t asPe t Taio8chnk0a at g8ne0 ee8d0 Data To Be Submitted onditions (https://onlinelibrary.wiley.com 4.8 Storage of Files At The Fda 81 /term 5 4RS.ce9rf eeerennRsc eiencso Sm8a1mfeetnyd aendd R Hegauzlaartdor Ay sRseesssomurecnets 81 83 s-and-conditions) on W 555...312 UICnhsteraosr daocuftc eStriciosrntei ec8ns 3so f8 S6creens 84 iley Online L 55..54 C5T55...yr444ip...t123eesr i oonf SST:S Dieicneqrergeu vle(eeeonn lrSsot iMtpaa8mlgu7 eel8t n7is8t t7Aagned) U8s7e 87 ibrary for rules of use; OA 55R..e67f erenAU5555c....nn7777eai....sv1234l ya 9rsi2iast CCMTeO hoeDfunen lSa tttArritcvaaornla le a rT8eClino9eahntigenad rPgDet lsnDoa ctt8ay at9 9aP91 l08o8ts 90 articles are governed by the applicable C reative C om m ons L icense D ow xii COnTEnTS nloaded from 6 F66..o12r muIM6lna.2tetr.ico1ohd nausnc,i tsRLimooonscu at99le 57sE,f afencdts D 9o7sage Regimens 95 https://onlinelibrary.w 66..22..32 MAbestaobrpotliiosmn a n9d9 Distribution 98 iley.com 6.3 C66..o33m..12m onDP Raeroremunttaeelsr Ra9lo 9Rutoeu t9e9s 100 /doi/ by ibrahim 6666....3333....4563 BOMRoorialnuulot seRr vCoReuoortmsueu tpes1a sI0 rni31sf1ou1nsiso ann d1 0C2ontrasts 113 ragab - Cochrane Germ 6.4 6F.o4r.m1 ulatPiorne fOorfm Tuelsatt iMona te1r1ia4ls 113 any , W 6.4.2 Dermal Formulations 117 iley O 6.4.3 Interactions Between Skin, Vehicle, and Test Chemical 119 nline L 666...765 EC6D6..xao44cls..c45iipun ilgea ntCitOPnasga lrcr a1Meul2n lF3aateottierroraminla suFl loRa1rt2emioq2unulsiar et1imo2ne0sn ts1 21122 ibrary on [14/01/2023]. S 6.7.1 Regulation of Excipients 123 ee the T References 128 erm 7 M777...123e cha777MME7n....ni3333aesd....ncm1234 hiP fsaoe nAsinitsnaCBFCtmstdololi iioMo sdnnEn dyOiiesncc a aWfaadn s1llT udeP3OSori 1oWgiexbgidhisnnca teIssittrntes vyr 11OaG C33t1ief23oo3 nDnn2essrru aum1lg 3T pT2otoixoxincici ti1yty3 S 3tudies 132 131 s and Conditions (https://onlinelibrary.wiley.com 7.3.5 Clinical Chemistry and Pathology 136 /term 777777......333333......891671 0 1 HOCHGnaiperesormuhtdsrotiasohpo ttanoavoltlamxehosciogoccrlyuolooo llpgaog1syrgyy3 Fy 7a1 1un314nd740c t0Oiorng a1n4 W0eights 137 s-and-conditions) on Wiley O 7.3.12 Immunotoxicology 140 nline L 8 7RP.ie4lfo etr Ten7Coc.xo3eim.sc1 ip3t1yl i4 cT1aIetmisotaingnsig n 1gI4n a1 nDdr uTgel eSmafeettryy E1v4a1luation: MTD and DRF 143 ibrary for rules of use; O A 888...312 A88IR8n...ac322trnu...o112gted e u-S FcytiMLUTisnotehdsenitieinmh nn iMa1ggmicl4 iRSi at3Tnylta oiu AnmTxdgceiiuceeusmi-sttti Fe yn Li1 TgnC4e od3th1xihna4iacrg4lai tDcLyte oeTtrsheiezas alt1i tti51yo05 nD3 a1t5a3 in Drug Development: articles are governed by the applicable C reative C om m ons L icense