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UCD ISHEALTH SYSTEM2010 IND/IDE Lecture SeriesAugust 27, 2010: IND Process and General Responsibilities underIND and IND ExemptionsA. Accessing InvestigationalClinical TrialsAnticancer Agents Outside ofVol 55 April 11998 Am J Health-Syst PharmB. TreatmentIND: Letter of Cross ReferenceC. Decision Tree: Is An InvestigationalApplication Required?D. Self- DeterminationNew Drug (IND)of IND ExemptionE. IND Exemption LetterF. IND WithdrawalLetterG. Protocol Development:Table of Contents TemplateH. Registering a Clinical Trial in ClinicalTrials.govChest 2007; 131:909-912

UES1: ONS& NSWERSAccessing investigational anticanceragents outside of clinical trials.QWhat treat entoptions are available for cancer patients whose disease hasprogressed after standard therapy and who areineligible or unable to participate in a clinical trial?A.The Division of Cancer Treatmentand Diagnosis (OCTO), National Cancer Institute(NCI), allows early access toinvestigational anticanceragent.s for patient.s who areunable to participate inclinical trials. Early access isprovided through severalmechanisms. including spe-cial-except.ion, group C,and treatment referral centel' (TRC) protocols. !nvestigational agents obtainedthrough the early accessprogram are sometimes described as being for nonresearch, or compassionate,use. The ultimate purposeof t.his program is t.o makeavailable to individual cancer patients and theirphysicians investigationalanticancer agents thathave not.able clinical activit.y against specific malignancies.Physicians who want t.orequest an agent for nonre-The Questions and Answers column fea/llres ASH? slarr responses 10mqwnes from pharmacisls in Iwalth systems. Through this column,more praclilioners may benefil from the answers prepared by rhe srarrThe column may also include answels soliciled from olhers: includinggovernment agenCIes such as OSI-IA. FDA, and DEA.Pharmacisrs with questions for ASH? should ""Tire direclly 10 rheappropnale slaf! member, nor AjIIP. The headquarters slafforganiza·lion published in the August 15, /997, issue ofAjllP Ii.sts thc names ofall slaffmembersaccording /() area. Frequemly called extensions arclis red in every issue ofAjllP on rhe pagc alier'rlJe Table ofeomenls.search use lTlust considerthe following questions: Is the patient ineligible orunable to be treated on aresearch protocol? (Patl'ellts ShOllld be' lI1eI'Igi'bl eor unable to pankipate ina clinical trial for reasonsother than safety.) Have standard therapiesbeen exhausted?Is there oqje-Cliveevidencethat the invesligationalagpnt is active in treatingthe disease for which therequest is being made'?(Published data fromPhase- II trials arc usuallyrequired as objective t'vidence of activity.)Is the drug likely to benefitthe patient while posingacceptable risk?A request for nonresearchuse may be considered byOCTO if the answer to ailthe above questions is affirmative. Each mechanismfor nonresearch use differsin purpose and in the reporting and procedural re-sponsibilities of the investigator.Mechanisms for earlyaccess. Special exception.The special-exceptionme-chanism is the functional e-quivalent of an emergency investigational newdrug application (INO) except that any person registe-red with NCI as an inve-s-tigator may obtain an agentdire-ctly from OCTO insteador having to have an lNOapprove-d by FDA. A requestfor a special exception maybe considered 1'01' any investigational agent for whichOCTO sponsors an IND.OCTO currently sponsors1110rethan 200 INOs withFDA for approximately 150differe-nt investigational anticance-r agents. Approvaldeppnds on me-eting thestandard criteria for nonresearch release of investigationa! agents as previouslyc1iscusse-dand agent availability. Requests for specialexceptions arp revipwed andapproved by staff of theCance-r Therapy Evaluat ionProgram (CTEP) on a palient.-by-patipnt basis.Group Cor trealmemIND.OCTO requests group C ortreatment INO designationfrom FDA for an investigational agent that has reproducible efTicacy in one ormore spe-cific types oftUlllors: Such an agent isconsidered likely to alterthe contemporary treatment or a disease and canbe safely administered byproperly trained health careproviders without specialized supportive care facilities. Typically. OCTO willse-ek group C classificationonly for those agents whoseactivity is well-enough established that FDA approvalof a new drug applicationor biologic license application is likely in the- relal ive-Iy near future. If an age-ntmeNs these cril('ria, OCTOmay initiate a formal application to FDA 1.0 aut hori7.(,group C distribution for aVol 55 ApI' I 1998 Am J Health-Syst Pharm 651

Questions & Answersspecific indication. Suchapproval is not equivalentto formal FDA approval ofefllcacy of that agent forthat indication. Any registered investigator may receive a group C agent. NCIhas sponsored more than20 group C protocols since1976 (table). At the time ofwriting, the only activegroup C protocol is for azacitidine for the treatmentof refractory acute myelogenous leukemia.Treatmenl referral centerproloeal. OCTO may makeinvestigational treatmentsavailable via a TRC protocol for certain highly promising agents or high-priority diseases such as breast.prostate, lung, and ovariancancer. TRC protocols canalso be used to ensure equitable distribution of agentswith limited availability.Safety and efficacy data arelypically collected in TRCprotocols. TRC protocolsare initially offered to theNCI-designated clinicaland comprehensivecancercenters. All patients treatedon a TRC protocol must receive their investigationaltherapy at an NCI-designated cancer center. NCIarranged for three TRCprotocols, now completed,that used paclitaxel in thetreatment of refractoryovarian cancer (TRC-91 03)and refractory breast cancer (TRC-9202 and TRC9301).NCI treatment referralcenter. All requests for ('ar-ly access to OCTO-sponsored investigational chemotherapeutic agents arcconducted through NCI'sTRC. The TRC is managedby the Pharmaceutical Managem('nt Branch (PMB),CTEP, OCTO. PMB is composed of nine clinical research pharmacists. TheTRC is coordinated by aPMB pharmacist. Each PMBpharmacist has experiencefielding TRC questions.The TRC is a means forNCI to provide informationto community oncologistsand other health care professionals about therapeuticoptions for cancer patients.The TRC uses several resources, such as PhysiciansData Query and the CTEPinformation system, tomaintain a referral list ofthe most current active research protocols. The firstpriority is to refer patientsto cooperative-group orcancer-center t.rials. If a pat.ient. is unable to participate in a clinical trial, anonresearch mechanismmight be considered.Healt.h care professionalsmay cont.act t.he TRC about.potential therapeutic options-clinicalt.rials ornonresearch programs-bytelephone (301-496-5725)or by fax (301-402-4870).Procedures. NCI has at.tempted to simplify the acquisition and managementof investigational anticancer agents for each nonr('search program previouslydescribed. NCI has designed policy and procedures to expedite the review, registration, approval,and distribution of nonresearch agent.s and the protocols for treating patientswith these agents. TheCTEP home page (http://ctep.info.nih.gov)containscurrent. information. policies, and procedures relat.edto OCTO nonresearch activities and ot.her programs.Ext.raneous paperwork hasbeen eliminat.ed. and, whenpossible, st.andard reportingmethods arc used. PMBpharmacists can assisthealth care providers in addressing t.he medical, regulat.ory. and administrativerequirements associatedwith nonresearch protocols. All investigationalagent.s are provided byOCTO at no cost 10 thephysician or patient (shipping costs are borne by thereceiver).Submission of reques .652 Am J Healt h-Syst.Pharm Vol 55 ApI' I 1998While group C and TRCprotocols have set criteriato determine patient eligibility, each request for aspecial exception is assessedon it.s own merit. The following information is required for NCI t.o properlyevaluate each request.: patient. identifier (initials oridentification number), age,sex, diagnosis, previouscancer therapy, currentclinical stat.us, intendeddosage and schedule of therequested agent (accordingto t.he current. lit.erature),potential concomitant therapy, and pertinent laboratory data.Each case is reviewed andass('ssed on t.he basis of established guidelines dev('loped by st.aff oncologist.sand derived from publishedliterature. St.aff oncologist.sare consulted about requests that fall outside theguidelines.Every attempt. is made toprovide request.ers with aresponse as quickly as possible. Typically, requestersarE' notifird of a decisionthe same day. and, if use ofan invrstigational agent isapproved, thE'Ycan oftenobt.ain the agent via a nonresearch mechanism withinthree to five days. In theevent of a medical emergency, investigationalagrnt.s may be shipped fornrxt-day or even same-daydelivery. All establishedCI policies on drug accountability and st.orage ofthe agent must. be adheredt.o. A separate drug account.ability record should bemaintained for each nonresearch protocol.Treatment guidelines forgroup C and TRC prot.ocolsare provided. Occasionally,treat.ment guidelines arealso provided for specialexception protocols. Thehealth care providers requesting the investigationalagents are requirrd to complete a special-exceptionprotocol document if treat.-ment. guidelines are not.available. The specialexcept.ion protocol document includes a brief patient hist.ory. a descriptionof the t.reat.ment plan, dosage modifications. andmonitoring variables. Patient. treatment should bebased on published reports.The completed special-exception prot.ocol documentshould be signed and ret.urned to the PMB within10 working days. A copy ofthe special-exception protocol is submitted to the appropriate INO file.FDA form /572. FDA andNCI policy requires all people functioning as investigators who participate in aOCTO-sponsored tria!, including nonresearch studies. to have an FDA form1572 (st.atement. of investigator) and a current curriculum vitae on file with thePMB. Investigat.ors areasked t.o provide t.heir office. shipping, and institutional review board (lRB)addresses on the lonn.CTEP has attempted to expedite and simplify investigator registration as muchas possible. When necessary. new investigators canobt.ain registration wit.hin24 to 48 hours.IRB and informed consent.FDA and NCI require thatapproval by an IRB and informed consent be obtained before a patient istreated with an investigational agent. NCI providesmodel informed-consent.forms lor group C, TRC.and some special-exceptionprotocols. The IRB requirements dilfer slightly foreach nonresearch mechanism. Approval by an IRB isrequired before activationof a TRC protocol at a participating instilution. Awaiver of the requirementfor IRB approval may be obtained from FDA lor groupC protocols. Group C proConlillued on page 660

Questions & AnswersConlinuedthat written documentation of IRB approvaland asigned informed-consentform be ret.ained in the patient's medical record forfut.ure reference,Adverse drug events, Investigat.ors are required t.o submit adverse event report.s toCTEP for all agents obtained via a nonresearchmechanism,Investigat.orsshould use t.he Phase II andIII guidelines,included withthe special exceptionpacket, for reportingadversedrug reactions. The NCIcommontoxicity criteria table should be consultedforadverse event report.s.Final reporl. NCI requiresa final repon for all patientstreated on nonresearchprotocols. The informationrequired for a final report isfrom page 652tocols are reviewed and approved by NCT's IRB, Althoughlocal IRBs arc notrequiredto review group Cprotocols,they retain theright to do so, Regist.eredinvestigat.orsare encouraged to contarltheir localIRB t.o determinethe institutionalpolicy on IRB review of group C prot.ocols,IRB approvalis also required for special-exceptionprot.ocols, NCI docs not.specify how or in whatform IRB approvalis to beobt.ained (e,g" full IRB, IRBchair only), The local IRBmay set whateverpolicy itdeterminesis appropriat.efor approvalof specialexceptionprotocols,However, NCI policy requiresCancer Therapies Provided through the Group CTreatment Protocol ichia nth C1 ndY C1 of AJ?pro\iClIIND"Group CNDNAf.lr '76ApI' '76Aug '76Aug '76Aug '76Aug '76May77Oct '76Active group CMay '80IND wlthejrawnJun '82Jan '58Jul '71Jun'63Ocl'75Jul '77Jul '77ApI' '78Dec '78Fell '91Mar '71Sep '72Scp'78Aug '77Feb '78May '78Oct '80Dec '81IND withdrawnOct '83May '86IND withdrawnFeb '84Jan'87Jun '79Sep '72Feb '77Nov 82Dec '91ApI' '84May '87Dec '87Jui'88Oct '88May '89Oct '89MeH'92Jul '92May '92Dec '88Feb '92Oct '92Jun'90Dec '91Mal '93Dec isplatinHexalnetllylamincAsparaginase(fromErwima rleukin·2 and LAK"cellsIfosfamide and neChlorodeoxyadcnoslnePaclrtaxelIND 1I1v[ 'IIYdllondl new druy application'NDAnew clluy applicationPreViously known as ,tl eptozotoCin'LAK iymphok"""'dctlvatedkiliel660 Am J Health-SystPharmVol 55 ApI' 1 1998usually minimal.Standarddata-collectionforms havebeen developedfor group Cand TRC protocolsand several special-exceptionagents, A generic dat.acollectionform (Report ofthe IndependentInvestigaLOr), alaso includedwitht.he special exceptionpacket, can be used for mostspecial-exccptionprot.ocols,Publication of a pa·tient's experience. Theprincipalpurpose ofDCTD's nonresearchprogram is t.o increase patientaccess to promisinginvestigational anticanceragents,not. to obtain clinical data,since Iimit.ed informationon drug efficacy and safetycan be obt.ained from thist.ype of research design,NCI has, however,published t.he results of severalgroup C and TRC protocols, I -, Because t.he eligibility crit.eria for group C andTRC protocolsare usuallymuch less stringentthanthose for a clinical trial. theresults are often describedas being more representative of t.ypical practicesettings, Given that. eachspecial-exceptionrequest isreviewed on its own meritand considereda separateprot.ocol, publicationofspecial-exceptiondatashould be limit.ed to casereports and anecdotaldataand should be accompanied by a clear statementthat patients were treatedon separate special-exception protocols,"Croup C c1assiricmion ,lntipreceded Ihe FDA regulations\ real mem I D prolocols by Iyears. In till' 19705. anticanceragpnh were e lassil'ied by NCIthn:'(-' ralegorjE' : A. 1-3,{]lId C.u crnrIintoI, Trimble EL. Adams JD, VenaDA e\ al. Pal'l iraxcl rorplatinum refractory ovariancancer" results from the first1000 patients registt'red toNational Cancer Instilut.eTrC'aullrnt Referral Center(TRC) 9103. J Clin Oneal,1993: 1 12405 10.2 Abrams JS. Vena DA. Baltz J et31. PaclilCt: el activityilllIeavily pretreated breastcancer: a National CancerImeitute TreatmentRererralCemer trial. J Clin Onco/.1995: 132056 6S3. Sorensen JM, Vena DA.Mnmello MJ et al. Treatmentor hairy cell leukemia (IICI.)with 2 chlorodeoxyadenosine(CDA) under the group Cprotocol mechanism. PrO(' AmSoc Clin Oneal, 1993: 12:302.Abstract 988.4, Light SF, Stevenson HC,Parkinson DR et al. Phase IItrial of all trans rcrinoic acidin acute promyelncyticleukemia, Proc Am Soc ClinOneal. 1992: I I :263, Abstract861S, Sorens"n JM. Chun HG, VenaDA et al. Pemmtatin(DCF)therapy ror hairy cell leukemia(lICI.). update or a group Cprotocol or 208 patients whohave failed interferon alpha(I FNa). Proc Am Soc Clio Oneol.1991. 10'232 Abstract 787Michael J. Montello,M,S .Hl'ad. Protocol andInformationOfficeJay]. Greenblatt,Ph,D"Head. Regulatory AffairsDrug/SectionAlfred Fallavollita,M.S"Chief. PharmaceuticalManagementBranchDale Shoemaker,Ph,D"Chief, Regulatory AffairsBranchCancer Therapy EvaluationProgramDivision of Cancer Treat mentand DiagnosisNational CancN InstituteExeculivl' Plaza NorthHoom 707Bethesda, MD 20892montellom@ctl'p,nci,nih.gov

Wyeth PharmaceuticalsP.O. Box 8299Philadelphia, PA 19101-8299David K. Ellis, Ph.D.Assistant Vice PresidentGlobal Regulatory Affairs(484) 865-5237ell isd2@"'yelh.comWyethApril 3, 2009IND 55,830TORISEL (Temsirolimus,IntravenousSerial Number 1018CCI-779)Other:Letter of Cross ReferenceRobert Justice, MD, DirectorDivision of Oncology Drug Products (H FD-150)Attn.: Central Document RoomCenter for Drug Evaluation and ResearchFood and Drug Administration590 I-B Ammendale RoadBeltsville, MD 20705-1266Dear Dr. Justice:Wyeth Pharmaceuticals, Inc. hereby authorizes the Food and DrugAdministration (FDA) to reference IND 55,830 for TORISEL in support of anInvestigational New Drug Application (TND) to be requested byMD, UC Davis Cancer Center, 450 I X Street, Sacramento, CA 95817 toconduct the following protocol:Protocol 3066K 1-1207, "Phase I Trial of Pazopanib Plus Temsirolimusin Advanced Solid Tumors, with Emphasis on Renal Cell Cancer:'The cross-reference will apply for all relevant clinical, preclinical toxicologyand pharmacology information, as well as chemistry, manufacturing andcontrols information submitted to our IND. However, the information in ourTND remains confidential; this letter of authorization is not intended to permitthe above-mentioned parties or any others to access the data in our IND, or anycomponent of it without the expressed written consent of Wyeth.

TORISEL (temsirolimus)injectionIND 55,830, Serial No. 1018April 3, 2009Page 2 of2This submission is provided entirely in eCTD format, therefore no table ofcontents is being provided. The FDA Viewer will display the content of thesubmission in its correct CTD location. Information related to the electronicformat of this submission is provided immediately after the signatory page.Because this submission contains highly confidential information and tradesecrets, we request that it be withheld from disclosure under the Freedom ofInformation Act pursuant to 2) CFR § 20.61. We further request that if theFDA tentatively determines that any portion of the submission is disclosable inresponse to a request under the Freedom ofInformation Act, that we beprovided with the opportunity for prior consultation in accordance with 21CFR § 20.47.Should you have any questions regarding this submission, please do nothesitate to contact Elena Spanjaard at (6) 7) 665-7365 or me at (484) 865-5237.Sincerely,David K. Ellis, PhDAssistant Vice PresidentGlobal Regulatory Affairscc:MDThis electronic submission is approximately 2 MB in total size. All files werechecked and verified to be free of viruses using VirusScan Enterprise, Version8.0.0 with a virus definition date of March 23, 2009.Technical questions, related to the electronic submission format, should bedirected to Taryn Stevens at (484) 865-8027.

Is an InvestigationalNew Drug (IND) ApplicationA product that is (i) intended for use in thediagnosis, cure, mitigation, treatment, orprevention of disease and acts throughmetabolism, chemical reactions, or the like; (ii)recognized in the US Pharmacopeia, officialHomeopathic Pharmacopia, National Formulary;(iii) intended to affect the structure or function ofthe body and acts through metabolism, chemicalreactions, or the like; or (iv) a component of anyof the above is a drug.Note: Studies involvingdrugs but exempt from INOrequirementsstill are subject to other FDA regulationsincluding21 CFR part 50 (human subjectsprotections),part 54 (conflictof interest requirements),and part 56 (IRSrequirements).No INO is required.Required?Will a drug be used,administered, applied, orimplanted to subjects?Foods and dietary supplements generally are notregulated as drugs. However, those that areintended or promoted to be used in the diagnosis,cure mitigation, treatment, or prevention ofdisease are considered drugs.yNo INO is required.Is the study an exempt studyof an in vitro diagnosticbiological product?NNo INO is required.Is the drug under studylawfully marketed in the U.S.but under investigation foroff-label indications andmeets other exemptionrequirements for off-labelresearch use?If the product (i) is blood grouping serum, reagentred blood cells, or anti-human globulin; and (ii) isintended to be used in a diagnostic procedurethat confirms the diagnosis made by another,medically established, diagnostic product orprocedure, it is exempt from INO requirements aslong as it is shipped with special labelingrequirements. See 21 C.F.R. § 312.160.The investigation is not intended to be reportedto FDA as a well-controlled study in support ofa new indication for use nor intended to beused to support any other significant change inthe labeling for the drug;If the drug that is undergoing investigation islawfully marketed as a prescription drugproduct, the investigation is not intended tosupport a significant change in the advertisingfor the product;The investigation does not involve a route ofadministration or dosage level or use in apatient population or other factor thatsignificantly increases the risks (or decreasesthe acceptability of the risks) associated withthe use of the drug product;The investigation is conducted in compliancewith the requirements for institutional reviewset forth in part 56 and with the requirementsfor informed consent set forth in part 50; andThe investigation is conducted in compliancewith the requirements of 312.7.Refer to the in vivo bioavailiability/bioequivalencestudy decision tree.Is the study an in vivobioavailability orbioequivalence study?An INO is necessary.Note: If the study involvesthe useof a placebo and is otherwiseexempt, it does not require an IND.

UNIVERSITY OF CALIFORNIA,BERKELEY'DAVIS'IRVINE'DAVISLOS ANGELES'HIVERSlDE SANDIEGO'SANFHA:-lCISCOSANTARAHRARA SANTACRUZUNIVERSITY OF CALIFORNA, DAVISCANCER CENTER450 J X STREETSACRAM ENTO, CALIFORNIA 958 J 7Date:May 5, 2009Study Title:UCDCC#218:Assessing PSA Response in Low Dose Ketoconazolein HormoneRefractory Prostate Cancer Patients Who Have Failed at Least One Prior SystemicChemotherapyRegimenUCD IRE No:200916901PrincipalPrimo N. Lara, Jr. MDInvestigator:Co-Investigator:JenniferMarie Suga, MDSubject:InvestigationalNew Drug (IND) Application Status as DeterminedIND Exemption UCDCC#218 (under 21 CFR 3 12.2(b)( 1»By Investigator-In accordance with the Guidance for Industry IND Exemptions for Studies of Lawfully Marketed Drug orBiological Products for the Treatment of Cancer*, it has been determined that the Investigator-InitiatedStudy UCDCC#218: Assessing PSA Response in Low Dose Ketoconazole in Hormone RefractOlY ProstateCancer Patients Who Have Failed at Least One Prior Systemic Chemotherapy Regimen meets all of thefollowing conditions for INn Exemption Status. The studies are not intended to support FDA approval of a new indication or a significantchange in the product labeling.Study Investigator(s)are not seeking FDA approval of a new indicationor a significant change in the product labeling for Ketoconazole. The studies are not intended to support a significant change in the advertising for theproduct.Study Tnvestigator(s) are not seeking to support a significantthe product, Ketoconazole. for Ketoconazolechangein the advertisingforInvestigators and their IRBs determine that based on the scientific literature and generallyknown clinical experience, there is no significant increase in the risk associated with the use ofthe drug product.Study Investigator(s)and the University of California Davis Institutional Review Boardhave determined that there is no significant increase in the risk associated with the use ofdrug product, Ketoconazole.A sampling of published data on this topic is attached.Page I of2

The studies are to be conducted in compliance with IRB and informed consent regulations,pursuant to parts 50 and 56.This study will be conducted in compliance with University of Cali fomi a, Davis IRBpolicies and guidelines. See attached IRE Notice of Approval and IRE-approvedinformed consent. The studies will not be used to promote unapproved indications, in compliance with § 312.7.This study will not be used to promote unapproved indications, in compliance with §312.7.Primo N. Lara Jr., MDPrincipal InvestigatorJennifer M. Suga, MD MPHCo- Investigator* Guidance for Industry I D Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment ofCancer Page 5 Section IV. Determining Application Status B. Investigator Determination.Page2of2

10/06/2008IaJ 0021004FDA/CDER/OND/ODEVI/DRMP14:19 FAXDEPARTMENT OF HEAL TI & HUMAN SERVICESPublic Health ServiceFood and Drug AdministrationRockville. MD 20857IND 103445v1.D.University of Calif ami a, Davis Cancer Center4501 X Street. Suite 3016Sacramento. CA 95817Dear Dr.We acknowledge receipt of your Invest. ational New Drug Application (IND), submittedSeptember 03,2008, for Tarceva (Erlot: lib, OSI-774) in a study entitled "Phase II Study ofGemcitabine and Intemlittent Erlotinib in I,jvanced Pancreatic Cancer,"After reviewing the information contair ,:d in your submission, we have concluded that yourstudy meets all of the requirements for l: emption from the IND regulations and, therefore, anINO is not required to conduct your inv( stigation, In accordance with 21 CFR 312.2(b)(4) of theregulations. FDA will not accept your ar'plication,The IND regulations [21 CFR 312.2(b). state that clinical inve:;tigation ofa drug product that islawfully marketed in the United States i exempt from the requiremcnts for an IND if all of thefollowing apply:I.The investigation is not intendec to be reported to FDA as a well-controlled study insupport of a new indication for l:;e, nor intended to be used to support any othersignificant change in the labeling for the drug.2.The investigation is not intendelprescription drug product.3.The investigation does not illvol',e a change in route of administration, dosage level, orpatient population, or other factc 1 that significantly increases the risks (or decreases theacceptability ofrisks) associated .vith use of the drug product.4.The investigation is conducted ill compliance with the requirementsreview (21 CFR Part 56) and inhl11ed consent (21 CFR Part 50).5.The Investigation is conducted ill compliance \vith the requirements of 21 CFR 312.7,i.e., the drug may not be represented as safe or effective for the purposes for which it isunder investigation. nor may it b; commercially distributed or sold.toSUPPOl1a significant change in the advertisingfor afor institutional

10/06/2008 003/004FDA/CDER/OND/ODEVI/DRMP14:19 FAX[ND 10.3445Page 2In addition, 21 CFR 312.2(b)(5) exemr'ls from the IND requirements a clinical investigation thatinvolves use of a placebo if the investig ilion does not otherwise require submission of an IND.We remind YOll that exemption from thi requirements for an fND does not in any way exemptyou from complying with the requirem:nts for informed consent under 21 CFR 50.20 and initialand continuing Institutional Review BC':lfd review under 21 CFR Part 56.For additionalregulations.information,you can clw·;k our web site at http://www.fda.gov/cderfor the INDIf you have any questions, call Frank H. Cross, Jr. CPMS, at 301-796-0876.Sincerely,Robe11 JustIce, MD.DirectorDivision of Drug Oncology ProductsOffice of Oncology Drug ProductsCenter for Drug Evaluation and Research

.v ""'''''ClI ""( -.ttt.DEPARTMENTOF HEALTH AND HUMAN SERVICES . -----------------------------------Food and Drug AdministrationSilver Spring M D 20993IND 066123WITHDRAWALAttention:IV, M.D.University of California Davis Cancer Center4501 X Street Suite 3016Sacramento, CA 95817IDear Dr. (Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)of the Federal Food, Drug, and Cosmetic Act for Yelcade.We also refer to your July 14, 20 I 0, letter requesting that this IND be withdrawn.We remind you that you must notify all clinical investigators of the withdrawal of this IND.We would also like to remind you that any unused drug must be disposed of properly.The withdrawal procedure is now considered complete. If this drug is again subjected to clinicalinvestigation, it is required that we be notified. This may be done by submitting a new IND.Information in this withdrawn IND may be included by specific reference. Withdrawal of anIND does not constitute abandonment of the application as provided by 21 CFR 312.130(b). Adetermination of abandonment is only made at the time a request is received under the FreedomofInformation Act and after consultation with you.If you have any questions, call me, at (30 I) 796-1381.Sincerely yours,Alice Kacuba, RN, MSN, RACChief, Project Management StaffDivision of Drug Oncology ProductsOffice of Oncology Drug ProductsCenter for Drug Evaluation and Research

TABLE OF CONTENTSPageSCHEMAi1. OBJECTIVES1.1 Primary Objectives1.2 Secondary Objectives12. BACKGROUND2.1CTEP IND Agent2.2Study Disease2.3Rationale2.4Correlative Studies Background13. PATIENT SELECTION3.1Eligibility Criteria3.2Exclusion Criteria3.3Inclusion of Women and Minorities.4. REGISTRATION PROCEDURES4.1General Guidelines4.2Registration Process.5. TREATMENT PLAN5.1CTEP IND Agent Administration5.2Definition of Dose-Limiting Toxicity5.3General Concomitant Medication and Supportive Care Guidelines5.4Duration of Therapy5.5Duration of Follow Up5.6Criteria for Removal from Study.6. DOSING DELAYS/DOSE MODIFICATIONS.7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS7.1Comprehensive Adverse Events and Potential Risks List (CAEPR)7.2Adverse Event Characteristics7.3Expedited Adverse Event Reporting7.4Routine Adverse Event Reporting7.5Secondary AML/MDS.8. PHARMACEUTICAL INFORMATION8.1CTEP IND Agent (NSC#)8.2Availability8.3Agent Ordering.1.IV

8.4Agent Accountability.9. CORRELATIVE/SPECIAL STUDIES9.1Laboratory Correlative Studies9.2Special Studies.10. STUDY CALENDAR.11. M EAS UREMENT OF EFFECT

HEALTH SYSTEM 2010 IND/IDE Lecture Series August 27, 2010: IND Processand General Responsibilities under IND and IND Exemptions A. Accessing Investigational Anticancer Agents Outside of Clinical Trials Vol 55 April 11998 Am J Health-Syst Pharm B. Treatment IND: Letter of Cross Referen

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