CLEARS Study SAE Reports by Stephen Olson

Universtry oF MINNESOTA Ambulatory Research Center Department of Pychintry Riverside Professional Budding ‘24h Avenne South Medica Shook 2h Minneapolis, MN S3435 August 25, 2005 Ms. Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota, MMC 820 D528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455 MOA |4 OMSO/4. Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPERDAL) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Protocol 50771L/0089, The CLEARS study Dear Ms. Webster, Tam writing to inform you of three Serious Adverse Events that took place at our site, ‘The first involves a male who was hospitalized due to an exacerbation of psychosis during the sereening process of the study. He withdrew his consent before taking any study drug, therefore the study drug was unrelated to this event. The second involves a female who was taking study diug after having been in the study for a few weeks. She, too, had an exacerbation of psychosis, She stabilized and continued to take the study drug, but eventually withdrew consent after discharge. Ido not believe that the stady drug was related to this event. The final event involves a femate who was also hospitalized as a result of an exacerbation of her illness, This subject had been experiencing increased stress and as a result used street drugs, at \which she brought herself to the emergency room, She was in the hospital for six days to stabilize, and was discharged with the same meds and follow-up chemical dependency treatment, [ do not believe that the study drug was retated to this event. Enclosed are the reports that were given to the sponsor. { apologize for not reporting these events mote promptly. ft took time to gather recons and work with the sponsor to complete the follow-up reports. Please notify Elizabeth Lemke (612-627-4364) or mysel! (612-273-9763) with any questions of concerns. Your continued support of this study is greatly appreciated. Sincerely, by {)boono— Stephtf C. Olson, M.D. Principal Investigator enclosure* pstrazenece Serious Adverse Event Report linical Study WM uaes PF inital Report " Brotoset Nog.) spel Site Nos Ole| [Counts OSA Jamie nvollment No. __| Randomization No Paton naa: WG Follow up Report he nla Weights 1 age: a TA Maie | Aoe 80 OFAN ai _ Hg r vi = ES - Serious Adverse Event (SAE): | Dato AE Started: (00S Bracecbetion af PssChosrs Date fit occurence of symotta rs sant Brief Description of SAE: Date t Serious C1 = Sond" (Syn, couse teabent 9 SAE} ate AE met Serous crea pees Ace besinniyy semused tn amy pe hienh boayiny expenencig Tin austen, NaAlWManahBAs, an) evenveiky quit bs yr Prker Ay date of SAE he Wud ben {9 ve meat ebay Move peels and wiv a WOOL ef | tostaleaten . 1 ‘mpatantmedeal rent in fis home. Re eventually SinShed “He | iftospitalized: — TY ond compet, ah whitin he agreed ty | Date of hospitalization: jee Bear Ha ermerseanGp Poni by Date of cischarge: HS weer: Ab aelmedsiCn fa evcivésed fT adsive Symptons pu \ ne setublat AE Stopped esalved) fet es HOM» or emit ideation, MO | sow tad er Inaive YMPHMS coca reported GS weld. | Outcome Le endersed Bcecswnd ox oF aleohe | | EP Reoverndhosied pot ne oral Scbstancss. Pld to hesptblise.| 7 rere cle Opti) Siable wth peydle medication | Elia Chane Parienk was Screened for studs Probable cause af death: Jou ¥ gaver fanden ped, Senened tir suet on scregn fed | on, set 8, pe gy Duration of Therapy Rowe | Daily | otal oomuanryces 2080 Product(s) |_| raze, | Freavonay | 230) Maeno ae em ier sesgioaes | “eel® | oaes.tiay | 9092 stated stepped in-patient nospratzaton or prolongation of eis (21 Persistent or significant disabittyrincapacty Vere wld Ming te de variensHadegs| E] Acoment!abtomenyiem ater { Aotopsy performed: — C} No] Yas (attach report) >00s~ pros Gatsaiy assessment (es orto) mont: hat ther sa reasonable porstaity tht ‘tha event may hava bear caused bythe dig?” 35 moninninaseei hinshetagatenot 3 ‘ May 2001 ~ Standard Operating Procedure CRIUS.O01.4 Invsigtana roa terporary spec gato, Cio [Yas Nat applicable 1Astrazeneca @ Serious Adverse Event Report — Clini tudy Be 1 \SAEF nial Report (Follow up Report Site No.! OOle ‘Country: FFE Glintrace Now: ol Randomization Nos AVA | Patents: “| Relevant Glinical Laboratory Assessments: (Ef Notpertormed | [Attached [See botow ony SAE tod segoasmant) _ ‘Assesses date” | Sample Toot Rasa iat Range | Astosamentdaie” | Sample Tost Wenut” | Reb Range | oosnenree {inde und Ciccone: opunmirey tet) (el | Reovant Gtr Teatng (reli dal of evan anes nia 20) Relavant Medical History: (e.g, concurrent diseases, previous history of present condlion, allergies, previous drug reactions) MN YKione pcmmord Lphery; v thes of Where Cad AO SY, hoy TOOT Lod a BD. Tey (AIS. Er ep mee iA CAPE Sivieg [Concomitant Drag Therapy (taken during last month) [J None _ Exclude medeines given tote fa 3 ae Eve, ror apse eae ge trond SAE fom Lem | Route |, oar | fall | euaonattneapy | causa | tiation for Ue of ‘es oe to oratly, rr) “Assossment seninicon | obcca | ASSES | 288. | aay Tae | “e xe) PO OS Te meg] Book Tives TN PO fan AIS | GO mney bed es re Lo. OG WD wy ear [oes fes LINO i | Cl yes CNo| [= Elves Chie — ~ F Dives Investigator name Skepren Olsen, P+. Address: (gy QUT Ave. S. Gute. LC® Minnecpous mn FSSA Name of Person & Wiwbeth Lemke . Reporting Event: ENe = eee ben At ics Phone number of —— Person Reporting V2 “e911 Ble} ent Signature: a 3/4/05 Tie oF Parson! Peart Cooldinalet Reporting Event: Date ofthis Report: 21a | 6 Date AZ Notte! { May 2001 ~ Standard Operating Procedure CRIUS-001.1 242)Astrazenece? Serious Adverse Event Repo! me Slinical Study tial Report 1 Follow up Report oor eee Fas los ‘rotocot No. ij (steno: Coe | Ter USA Clintrace No Enrolment? Randomization Noo Paton as Wash ibe ge sateotith a Haight ‘Serious Adverse Event (SAE): Eyaturta SO OP | Date AE Started: = ome | (wom daponsy ona mcen OMA eH [owe ote cearens oyna na art Brief Description Date AE met Serious Criteria: (Sots cr Hs 7 ee gins enter [paged study ceororator ) Dateoton Dat “LS C apps opin ering Sie Wil | sew rtenmesigi Ste Mas nents Se ACHES Wis te lite deepl her fo ao Sei > concer neck. Wi wegen’ care, iF smiches neediad ted that le eng bad vo oa was feeleng patsive conicl B avoranite she Weuldah oak ogg henied + vlanged by ki alle a we Viaclrctiat: < repoctte smo. He pee cs cenkrmed ‘The Event is Serious due to: Cy boat CO pitethreatening: erate nstataton ar praogason foes reopen Cy Porsistant or sinitcane dsabittyineapacty 5] Acongenial abnormatybith gefset, 1 Important medical avant (if Hospitalized Date of hospitalization y stiches reef + disoussect contact satety. Sverted@ te cove y for Srudy, visit Opies 1 cliseussed Phat sine. @ made. Stes < ew i Ne \ CAL ny per Wi ot epen ¢ Kraus ie epect a lot 7 | "Data of Death: Date of discharge: ‘AE Stopped:(if rosoived); to hen AB as peg et | ‘Outcome: 1D Recovorediesote EF Recoveringteasoving ] Not recoverediNot cesotved Ey RacouereaacoWved wih coq Cy ater Autopsy performed: C] No [1] Yes (Attach report Probable cause of death wicocl, “Asned her wrkt she expected (3 "i Tote [Bier ausatty | Action Fokon™ Froquency | Daily Assessment! 829 eg 9a, tiaj | F080 (Yes oF No) ‘or NIA) aa Cys ee ‘ausality Assossmont: 100 you consider tat thers isa vensonabie possibity tha te Qvont may hava been caused by the dg?” ‘ hay 2001 ~ Standard Operating Procedure CRIUS-001.1 - C Netappieatie ———} 1susa IAAL reper in thats pas pen, She stared Swill probably dle. Pica iclia OF hespbelunettien but wao arable é ney other suggesieth Safety plans rer Lude Getting in Mover @ family members and assuring trey would be monriorine her closely Sr. Wuchetith «writer aareed < convelted © 4 we believed hospttlizatian 2? be the rope ale hE of action . 2 arrangements: a fe FUN snp. 2 roby. Peter Miley, Univ. of syaniatric Staton (2 Mirmesetey pean IV) Keanty, Licsiy Parent was celwiled Gr ovicded leva” Trew, Se wed cok Waneif, “thd Gt Ach Gg sure pectienh fas hy ef csthing a cetking] ~ ya tent Geng Tetiiy 1S my of nigel ~ at THs parry bud net tolemich med te exter te Te rraie ey Ve tee (>) way. Sut jek vortheinew fren Shactig Continad teting aiperind on QP ~ acléltcl Uo 4) oF prilacAstrazenecd? Serious Adverse Event Report — Clinical Study __ gov Tels” Je Tntial Report [aj Follow up Report _rotocol No. STIL | 603i] Site Nox COLL Country: USA Glintrace No: Enrollment No.: Randomization No Patient initiate: Relevant Clinical Laboratory Assessments: EV Notperformed | [] Attached [OD Soe beiow (only SAE elated aseosements) ‘Sample Test & Rost Ral Range [ Assess date" Sampe Testa Rasa Ral Range [oommere | lh unt) Areude unt: | posses (etude uni) Antu uni | Rotovant hor Tas (noe ae oan and | Relevant Medical ison, 69 Since! Gates, prev jay Oise condone, revous deacons None Seb ytt Cried COPE Seeley wtih Oy cb Sturm tech ve DIC, & pomiceerh [oat se cal cork bbe, ne up orb! overeat ant te lind revonds athes ‘Concomitant Drug Therapy (taken during last month) [ None ue medics given to raat Swrious Adverse Event iLtnove space is eauted use sevand SAE for, — cou Dail Total Duration of Therapy Gausality,, | Indication for Use of SOE, | eithey | Bah ee se onto 0.00) | peer) [Seen ‘Stopes _| Te (ves Ene ~ ~~ | Bives EINe = ‘yes Ene | ——E [eyes Cine | = - Ghee CNe _ ‘CYes LiNe investigatorname: SfEphen C CSO ml aadress: cou 2HIm Cve-S, Surke G62) | oe Minneapois, MN 55454 [~NameaF Parson coe) eup | Wie at Parson — Gj Reporingevent Jean M1. Kenney, LCS | Reporting even © Phone nuraber of f Peron Reporing 6/2 W27- 36S “Ws! Batoote Reno 1 May 2001 ~ Standard Operating Prosecure CRUS-CO1.1 3aAstrazenecs? Serious Adverse Event Report Clinical Study jstay BP Total Report ‘Yt Follow up Report vaso aved SN (oy || Coming BA ‘inwac Enrollment No. Randomization No.: —__ Patient Initials: Weight 8 ge Date eh oie von ‘Serious Adverse Event (SAE): “| Date AE Started: ey (ain dagnoss EMACer bean OF Pagedros >, soars APO anete tig , aed Chem 2 HOG ato otis ovcurence of synptos,sed ene Brief Description of SAE: rhe peta’ Date AE met Serious Criteria: Brclescrionel SAR Gehnt ad hrs” owe Ae net safe cota: 30 aoaiirg whe T Shes OF Peon men Detection Date: occ” ricdliry Paved AsaC UE Od BOM ENE | asa uhenimmsigaar ts or ha ovr na SAE OF yA elect, Beptes © Cnet ONn any erent Soria deo: ° arti pagerond des kering The MME CN | 7 poaty Leeat deinking cet frieed ack | F) titetnestenng « JaneKed C4 ON Serre cites wattad HE 1 innate hesotataton or recombining fe ER ave HGS cecdineticd. “Hes a hoe OF | Fy Peete or siniteon iabityincepacty sek clapeneicnyy bt hay ok on EF Acongentalstonatyiit eect Gen Gen CASIO DOSS PE eR ospialzed: Vewey ani paarcia fev be44\ | Date of hospitalization . “ tert} @ASC AepRSSO DOR si vesetay Nene oe ceLmussiin (egies | Date of discharge: uae non. UP im toed From 90 OCR saad be increased Gigs Fete Mel) cana vere qeouck th Bla) 6% « 5-| Aexecsynnen A was oro a trait reteset oe geste oooh oyeat ‘Outcome: eed caecls Te Combiner, | Reomrearencved Ga wisn 0, Hueneme crtacecxed “ faa Fata" wet rete ad te “Date of Oeath: o o EDULE EEL] Autopsy prrmes: No] Yas fAtach reper) Seago rr? CC OE Probable cause of deat Rone | baly “ean aRaR RRR Gausniy | Action Taken Products) aon | Frequency | onsen erase assossmnent’ |“ (g 1.2,9 CRGISsgrerms? | EEF | esate (esertiy | orf) SSimraggepotmes” | “as Seed stoppea Bw) an | * causally Assessment: ‘Do you consider int tare is 2 reasonable possi tat the evertmay hove been eased bye a? EC) Nace Ste nso = lan Sods broken by nvoatigato®: KONo CI Yoe CY Net apeieblo 1 Nay 200 Senta Operating Peedi CRN. 005.1 1@Astrazeneca 2 Serious Adverse Event Report — Clinical Study aw Tesfos~__-APTallal Report (Ff Follow vp Repost (Protocol No a) 7M Janell Site Nez OO) | Counter CSA Glintrace No. Enrolment Ho. Randomization Na. Paton ia: Relevant Clinical Laboratory Assessments: TH Notperformed | E} Attaches |] Seetelow | ony SAE ltd assesment Assosrrt date | Sample 10018 Raval] Ral Range | RSSonew AS! Sal Tsk oat Wa Range |coamwrres | Gnd un Geeuse sy, | coun ecto __| eeciaey: | Rolovant Other Testing: (Include date of exam and result) Olen Felovant Modioal History: (eg. concurtant dacanea,prvious History of prosent colin, alleges, previous dup reactons) [nope Hy Cb cyreinctad Bependen 7 chan sober fo post t Yeo Mi ch ce mentee Rice Die aucek Foose ty teens enero elms TI None “farcl he reat Le Re on ye clit meines given feat Savous Aves Even more space a rela ue secre SAE fom. ve |. oaty | TH | puatonotmmenpy | cam. |ieatntrtmeor EEA, | regetey be Salt cone scene Sg aa (spect an) ‘Started ‘Stopped Soa) jax Estee i tes| Ove Gino [rated Bey | sy He Be [too on So — ee [Se ae? of Va a iavestigatr name: Seprer Signatweg slit ‘Fee lie Pes Address: (Gt uit Ave S$. Ste lb Minpeepeld, IW SS4SY omer SL Bin el "Title of Person Rane STREET Elia BE Lee ice Rasating event tes Cooutira te | Phone number of Chivlog seas Date ofthis Report s PersonRepoing d-W ATH Bey Date AZNotiied: [ite fos” Tes" | May 2001 ~ Standard Qporating Procedure CRIUS-001.1 2a)General IRB Contact Info University of Minnesota main line 612-626-5654 Research Subjects’ Protection Programs. fax 612-626-6061 ‘Institutional Review Board e-mail irb@umn.edu Expedited Review — Adverse Event Review] Time Sensitive Material Se ALA weyeqel 2. HSC # OOo aN hae Set-Up in X Re Date Matetial Was Received: ‘#1201 °% Pete see UP ier See Date Sent out to Reviewer Reiewe: OMY | eo ‘Needed Back in IRB Office By Comments to Reviewer: Review must be returned within one to two ae weeks of receipt of this, 2) Is the adverse event(s) off site? 3) Does the adverse event(s) involve the same protocat? 4). Did the adverse event(s) involve the same study drug? 5) Is the adverse event(s) already explained in the consent form? 6) Should the event(s) be added to the description of risk in the consent form? (lease outline recoumendation on back of page) 7) Should the IRB suspend subject accrual?UNIVERSITY OF MINNESOTA rin Cites Comps Research Suyacte" Protection Programs ddaya Mai Cte 820 osidsrabs tinal Rev Bor Haman uct Commins (Rd) SEB Move Menor ing ‘osinioatAsinal Care ad the Commates (INCU po baa oe A Stephen C Olson 120265650 Psychiatsy Department Pres. 612:526.6061 F28272A West B Soma Minneapolis Campus Nip search ama etet Mutjer RE: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractogenie Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia or Schizoaffective Disorter Protocol 50771L/0089" IRB Code Number: 03106453142 Dear Dr. Olson ‘The unanticipated problem and adverse event reports for the referenced study dated August 25, 2005 wore reviewed by expedited review and noted on September 23, 2005. ‘The following reports were included in this review: Please note that itis not necessary to wait to complete paperwork prior to informing the IRB of an adverse ‘event. The IRB should be notified at the same time as the sponsor. “Tho unanticipated problem and adverse event roports forthe roferonced study dated August 31, 2005 were reviewed by expedited review and noted on September 23, 2005. The following reports were included in this review: e000 Thank you for keeping the IRB: Human Subjects Committee informed of the status of your research. As Principal Investigator of this project, you are required by federal regulations to inform the IRB of any proposed changes in your research that will affect human subjects. Changes should not be initiated until ‘written IRB approval is received. Unanticipated problems and adverse events should be reported to the IRB office as they ovcur. Rescarch projects are subject to continuing review and renewal. Ifyou have any questions, or if we may assist you, please call (612) 626-5654, abc RLY Cynthia MeGill, CIP Exceutive Assistant CMlegk CC: Erica Carlson, Donald Doughiman, Kassia Fanezich, Jean Kenney, Mary Lawrence, Elizabeth Lemke, Phoenix Schmitz, Sellmann Schulz, John VucketiehUNIVERSITY OF MINNESOTA Olson soft CIIOMSBINL SAwvo8 ‘Poin idee Compr Department of Pescairy 292124 West Schizorreia Pron Abul Aoeareh Conter se 02 Mcapala, UN 55 sehen. ‘Stephan eo, ALD, rece Aatonate Passer ol Pyeraly orzzrasres ene ses isan Lamia MA, CORG, ‘anor Rasnaah Connie pizenr 36h annzasnaks Psbach Cordnaor sizer haba Joba Wehsteh MD, PRO. ‘Cournentgater Poe iy, HO, PD. ‘Covenenigalor ‘8. Chas Soh, MO. aparmant of Pashia 2430 Riverside Ave Momneapoie iN 99434-1495 fice: 612-273-9800 Medical School May 6, 2008 Ms, Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 0528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455 Re: “A muticenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPERDAL, in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Protocol 50771L/0089, The CLEARS study. Human Subject’s Code Number: Dear swsonebaca ey 11am writing to inform you of a cataractogeniic event for subject number that was found by one of the aphthalmologisis or, 2007. As per protocot, subjects receive eye exams every 6 montis during this 2-year study, and are examined by two ophthalmologists. During this eye exam, only one of the ophthalmologists identified that this was a cataractogenic event, while the other dl not. This information normally would have been followed up at subsequent exams, but the subject dropped out of the study shortly thereafter and has not hadl any followup. We only recently were informed that because this was detected at the last available visit, it ‘was considered a “cataract event* and clue to sponsor error in notifying us in a timely ‘manner that notification of the IRB was required. We have sent a letier to the patient fo inform him of this, and suggested that if he is concemed about it to arrange for an eye exam, Please contact me with any further questions regarding this matter Sincerely, Sloe bf Stephen C, Olson, M.O. Principal Investigator Driven to Discover’(28 AR, SIRTSORQ Olson | UNTVERSITY OF MINNESOTA | CRIOM S342 ‘etn Cites Campus Amibuatory Research Center Riseride Profesional Belg 606 24h Aver St Department of Poschicory 2 Medea! Schoo! Ste 602 Minmenpoli, MO SS6S4 May 5. 2008 Ofce: 612-827-4809 Ms, Patrice Webster rxecutive Assistant, Institutional Review Board University of Minnesota MMC 820 1528 Mayo Memorial Building 420 Delaware St. SI Minneapolis, MN 55455 Seta ti a is ces Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL) and tisperdone (RISPER- DAL) in the long-term treatment of patients with schizophrenia or schizoaffective roumasie disorder” Protocol 507711/0089, The CLEARS study. Human Subject’s Code Num- ore an a Dear Ms. Webster, Attached is a Note to File listing expiring study drug that was dispensed to study subjects trom 2007 to of 2008. The sponsor did not inform our site of this expiring drug until F £2008, and at that time subjects were given new study drug, {do not believe that the expiring drug caused any physical or psychiatric adverse events to study subjects ace C0, Please contact me if'you have aay questions or concerns about this mater. Sincerely, ©. Olson, M.D, Principal Investigator eacl,UNIVERSITY OF Trin Cites Campus M NESOTA Aimbaitory Research Center Department of Pychlatry Mesloa! Sohool Note to Fi Riverside Profextonal Bulldog 66 2 venue Souls Saute 602 ‘Minnsepots, MN 33482 Ofce: 612-627-4809 Listed below ate expired studly crug bottles that were dispensed and taken by study patients, The study drug expired on 7/31/07 but the sponsor did not notity the site of the expiring drug until February of 2008. Subiect # Batch # Bortl 87875 287875 87875 87875 87875 e7875 87875 87875 87875 87875 97878 7878 e7878 87878 87878 87878 87375 87875 87875 97875 97875 87875 64893, 64876 54981 4571 64689 64891 64578 84596 84983 64673 64281 64304 64287 64302 64289 64285 64600 64572 64573 64982 84674 84984 ispensed 71812007 711072007 81172007 95/2007 6726/2007 7128/2007 8/24/2007 9/26/2007 saer2007 2r1972007| 6/26/2007 712812007 8728/2007 8726/2007 1172672007 1211972007 7180/2007 8728/2007 72512007 10/26/2007 «13072007 1/30/2008 R 8/7/2007 81/2007 ‘ysr2007 20/1/2007 8/24/2007 ‘8/24/2007 9/26/2007 116/208 1116/2008 41672008, 6/28/2007 8/24/2007 ‘9/26/2007 1162008 162008 4116/2008 8/28/2007 9/28/2007 10/26/2007 41/30/2007 12/21/2007 2/19/2008 S 80 35 79 32 20 " med_Amiount_# Taken 75 0 45 1 48 60 69 82 5 30 30 30 30 30 30 38 42 60 58 38 20Committee Meeting Minutes May 28, 2008 Agenda Item: UPIRTSO. PI: Olson, Stephen Agenda Item: None ‘Agenda ftem: None | Protocol Title and HSC | the Cataractogenie Potential of ‘Queti | (RISPERDAL) in the Long-term Treatment of Pati | Disorder Protocol $0770L/0089" 0310MS3142 n of [tem Deser | The PL submits a UPIRTSO deseribed in the letter dated | who was identified to have had a eataraetogenic event by one study the subject should haye had followup, but the subject dropped out, obtained. A letter has been sent to the subject. The PI also submits a Discussion of Controverted Issues Summary: ‘As the contmifice did not knovr the content ofthe letter sent tothe st tunanticipated problem report had to be deferted ject or that the subject received the letter, this Revisions, Clarifications or Stipulations: ss Please provide a written response (o these points of concern: 1. The committee requires confirmation the letter has heen received by the subject. Ifnone exists, uequire sad confirmation. 2 inoo the committee iloes wot kiovy the content of the letter, confirm the subject has een warned that helshe ‘cannot take this rug in the future or risk dovelo 3. The committee noted the letter regarding ‘expiring drugs before notification from the sponsor. eataract. If not, the subject must be aware of this fact ve expiring drugs. Explain how the PL was not aware of the The committee wants to remind the PI that itis the PU’s responsibility Co identity and acknowledge wnaatieipated events and protocol deviations and act upon them ia. a timely fashion, Change tn Rist eneti Bal None ie ne TR Dean: Deter UPIRTSO ‘ont ts None Yoo ve wo iam) [Ret resADY PI: OLgon Awletcenter, Opea-Lobel, rie UNIVERSITY OF MINNESOTA Revi Schwaresiberg? Research Subjects’ Protection@rograms feeting Pate: 05/28/2008 Institutional Review Board If you choose to submit this form electronically, please send to irb@umn.edu. [Full Committee Review (Unanticipated Problem| {Criteria for approval under 45 CFR 46.111) ‘Type of unanticipated probie dverse Event: [ROn-site [Jofsite .ccidental/unintentional deviation from protocol without prior IRB review [Deviation from protocol without prior IRB review to eliminate apparent im [Jsatety monitoring report or interim finding that changes risk/benefit balance [Breach in confidentiality of subject data (Elsubject complaint Dother iate hazard Description of unanticipated problem: bake en Oerckure, SHA Arlcarrecd 10 We UN HE ede gs, = Nw plicae clock Deb dibyest Wenn 4 yor aod. “Do (hess eakaras ks woeeeke Oy Hic Osher We chs cpg. 6 (oy c Does the unanticipated problem meet the definition of UPIRTSO--Unant Problem Involving Risk to Sybjeets or Onase Check all that apply: [XSerious XJUnanticipate least possibly related Does the unanticipated problem meet the threshold for notification of Institutional Official? Re (Note in comments section) [No Has the risk/benefit balance changed? (Cl¥es. Ifyes, note in comments section how the balance has changed and whether risks to subjects are reasonable in relation to anticipated benefits.June 3, 2008 Stephen C Olson Psychiatry Department F2822.A West-B 2450 Riverside Minneapolis, MN 55454 RE: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractogenic Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia or Schizoaffective Disorder Protocol S077EL/0089" IRB Code Number: 031053142 Dear Dr. Olson: Notification of IRB Committes Action IRB Meeting: May 28, 2008 Item Under Review: UPIRTSO. IRB Action: Approval deferred pending receipt of additional information Additional Requirements Pending Approval: As the committee did not know the content af the lettet sent to the subject or that the subject seived the letter, this unanticipated problem report had to be deterred. Please provide a written response to Lhese points of concem 1, The committee requires confirmation the letter has been received by the subject. Ifnone exists, aequire said confirmation. 2. Since the committee does not know the content of the letter, confirm the subject has, been warned that he/she cannot take this drug in the future oF risk developing a cataract. if'not, the subject must be aware ofthis fact. 3. The cormmittee noted the letter regarding the expiring drugs. Explain how the PI was not aware of the expiring drugs before notification from the sponsor. The committee wants to remind the PI that itis the PI's responsibility to identify and acknowledge unanticipated events and protocol deviations and act upon them in a timely fashion. [your response is not received within 90 days, the study may be filed inactive ancl a new application required for futher consideration. Your response will be reviewed by the full RB committee. The IRB committee meets weekly; alist of meeting dates and deadlines ean be found on the IRB's Web site at http://www research. uma.cdu/irb/meetings/index.clm.If you have questions concerning this specific correspondence, contact Phillip Miner at 612-626- 5924. BS/pm CC: Donald Doughman, Belle Khuu, Mary Lawrence, Elizabeth Lemke, Kimberly Snyder, John VuchetichAGEN! University or Minwesora £208 Olson PRED CUPRTS) — gy OMsziya hin Gites Campus Ambltory Research Center Deparment of Psehairy Medial School July 30, 2008 Ms, Patrice Webster Executive Assistant, [nstitutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Building 420 Delaware St. St set Minneapolis, MN 55455 Re: “A multicenter, open-label, flexible-dose, parallel ractogenic potential of quetiapine Lumarate (SEROQU DAL) in the long-term treatment of patients with schizophrenia or schizoaffect Rivest Profesional Butaling 06 24h Avenue South Sue Mimeapots, BY $3484 fice: 612-527-4809 soup evaluation of the eata- .) and risperdone (RISP Re Tenens disorder” Protocol 5077IL/0089, The CLEARS study, Human Subject’s Code Num= ber: Dear Ms. Webster, ‘This correspondence is in response to your letter dated June 3, 2008, about the cataractogenic event and expiring study drug. [was unaware of the expiring study drug prior to sponsor notification because the drug does not contain the expiration date on the bottles, and information about this does not come with the shipping materials. 1 still do not believe that the expired drug causec! any physical or psychiatric adverse events to subjects. cit ALD. mail on Colmer twined to the post offfee to claim the letter, which was returned to me tything we could to inform the subject of this event, and since likely that he received our original leter, which in- he medication in the future due to the risk of de- vu is sibs believe that we did stake the subject has not moved, ‘eluded a warning about not taki veloping a cataract the fetter to the subject with the possible eataractogenie event was resent via extttied 2008. The subject was not home when it was delivered and never re~ is week. {n other news, we have completed all subject visits for this study, and anticipate study close-out by the end of this year, Sincerely, Sat Ole Stephen C. Olson, M.D. Principal Investigatorlawl V6 06 ST. August 25, 2008 Stephen € Olson Psychiatry Department8393 F282/2A West-B 2450 Riverside Minneapolis, MN 55454 RE: "A Multicenter, Open-label, Plexible-dose, Parallel-group Evaluation of the Cataractogenic Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term ‘Treatment of Patients with Schizophrenia or Schizoattective Disorder Protocol 5077110089" IRB Code Number: 031033142 Dear Dr. Olson Notification of IRB Committee Action IRB Meeting: August 21, 2008 Item Under Review: Unanticipated Problem Report IRB Action: Stipulations must be met before we can conclude review of this report Additional Requirements Pending Approval: Provide a written response to these points of concern regarding the unanticipated problem report for the referenced study received dated May 6, 2008, iavolving a Note (o File listing expiring study drug that was inadvertently dispensed to study subjects as a result of late notification by the sponsor Please respond to the following stipulation: 1. Provide a plan for preventing a similar occurrence, regarding expired drugs, in the fsture We cannot conchide review of this report until you respond to this request. Please re 90 days. pond within Please send your response to RSPP (Mayo Mait Code 820; D-528 Mayo Memorial Building; 420 Delaware St SE; Minneapolis, MN 55:55) The entire application does not need to be resubmitted; your response should address the sections requiring change. The signature of the Principal Investigator is the only signature required with the response. Only one copy of the response is necessary.4 ins doncerning this specific correspondence, contact Phillip Miner at 612-626- Research Conipliance Supervise BNSipm/ CC: Donald Doughman, Belle Khity, Mary Lawrence, izabeth Lemke, John VuchetichiVERSTTY OF MINNESOTA A, Prin Cities Camps Aimbelatory Research Center Riverside Professional Bulding . (2 Avenue South Department of Pspchatsy 608 2 Medical Schoo! Mianenpotis, BV 55859 (Ofice: 812-627-4809 August 27, 2008 Ms. Pattice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455 Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cata- tactogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPER- DAL) in the long-term treatment of patients with schizophrenia ot schizoaffective disorder” Protocol 5077IL/0089, The CLEARS study. Human Subject’s Code Num- ber: Dear Ms, Webster, This correspondence is in response to your letter dated August 25, 2008. You requested that we provide a plan for preventing a similar oecurren expiring study drug For the future, As previously stated. the sponsor noti expiring drug, and we pull that drug immediately after receiving that information, Because the expiration date is not provided on the study drug, we have no way of Knowing when the drug expires and rust rely solely on sponsor notification. After the sponsor realized that expired drug was inadvertently dispensed to subj taken to record all adverse events that (ook place while subjects were on expired There were not any physical or psychiatric adverse events at our site that were linked to the expired drug, regarding Please note that enrollment for this study is elosed and all participants at our site have completed the study, so we will not encounter this problem in the future. Please contact me if you have any questions or concerns about this matter (fae. Stéfhen C. Olson, M.D. Principal Investigator Sincerely,UNIVERSITY OF MINNESOTA Twin Cites Compas Research Subjects’ Protection Programs 0-528 May Manor! Dung 3?) ‘Rb deine see September 9, 2008 fee ofthe Vice President for Revere ‘epoli MAS3455 fice: 612-826-5654 Fe: 612-676-6060 Stephen C Olson Technet Psychiatry Department8393 Iedone eo beoma de F282/2A West-B 2450 Riverside Minneapolis, MN 55454 RE: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractogenic Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia ot Schizoaffective Disorder Protocol 50771170089" IRB Code Number: 0310M53142 Dear Dr. Olson ‘The IRB: Human Subjects Committee has received your response to its stipulations of August 2L, 2008. Since this information satisfies the requirement set by the IRB, final approval for the Unanticipated Problem Report is noted in our files. For your records and for grant certification purposes, the approval date for the referenced project is August 21, 2008 and the Assurance of Compliance number is FWA00000312 (Fairview Health, Systems Research FWA00000325, Gillette Children's Specialty Healthcare FWAG0004003). As Prineipal Investigator for this study, you are required by federal regulations to inform the IRB of any proposed changes to your research that will aflect human subjects. Changes should be eviewed and approved before they are initiated, Unanticipated problems and adverse events should be reported to the IRB as they occur. Research projects are subject to continuing review and approval Research Coi BNS/pm CC-Domat Doughiman, Belle Khutl\ Mary Lawrence, Blizabeth Lemke, John VuchetichStiga Rogan “Anbabtoy Reseeh Comer sao e02 Mice, 5454 renee sshinsbenicOuns.h aeons orza tes kup Colonie Scar eh Pros nd Degen 0 Piney > {VERSITY OF MINNESOTA Dadn Clos Campus Ambulatory Resear Center Riverside Prfessional Bulleng ; Lasts {06 24th Avenue South Departmen of Psychiatry + Metheal choot fae Nimsopli, 3075454 fie: 612-427-4809 ‘August 27, 2008 me Ms. Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455 Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPER- DAL) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Protocol 50771L/0089, The CLEARS study. Human Subject’s Code Num- ber: Dear Ms. Webster, This correspondence is in response to your letter dated August 25, 2008. ‘You requested that we provide a plan for preventing a similar occurrence regarding expiring study drug for the future, As previously stated, the sponsor notifies us of expiring drug, and we pull that drug immediately after receiving that information Because the expiration date is not provided on the study drug, we have no way of Knowing when the drug expires and must rely solely on sponsor notification. After the sponsor realized that expired drug was inadvertently dispensed to subjects, steps were taken to record all adverse events that took place while subjects were on expired drug. There were not any physical or psychiatric adverse events at our site that were inked to the expired drug. Please note that enrollment for this study is closed and all participants at out site have completed the study, so we will not encounter this problem in the future. Please contact me if you have any questions or concerns about this matter, (fao— ‘Stephen C. Olson, M.D. Principal Investigator Sincerely,tant Ve 2Ulof “PR August 25, 2008 Stephen C Olson Psychiatry Department8393 F282/2A West-B 2450 Riverside Minneapolis, MN 55454 RE: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractogenic Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia or Schizoaffeetive Disorder Protocol 50771L/0089" IRB Code Number: 0310653142 Dear Dr. Olson Notification of IRB Committee Action IRB Meeting: August 21, 2008 tera Under Review: Unanticipated Problem Report IRB Action: Stipulations must be met before we can conclude review of this report Additional Requirements Pending Approval: Provide a written response to these points of concer regarding the unanticipated problem report for the referenced study received dated May 6, 2008, involving a Note to File listing expiring study drug that was inadvertently dispensed to study subjects as a result of late notification by the sponsor. Please respond to the following stipulation: 1. Provide a plan for preventing a similar occurrence, regarding expired drugs, in the future. “We cannot conclude review of this report until you respond to this request. Please respond within 90 days. Please send your response to RSPP (Mayo Mail Code 820; D-528 Mayo Memorial Building; 420 Delaware St, SE; Minneapolis, MIN 55455) The entire application does not need to be resubmitted; ‘your response should adklress the sections requiring change. The signature of the Principal Investigator is the only signature required with the response. Only one copy of the response is necessary.CC; Donald Doughman, Belle Khtty, Mary Lawrence, Elizabeth Lemke, John Vuchetichas piuh O}son Untverstry oF Murnesord Saute o Dy (upriTs ) OBIOMSZIy 9, ‘win Ces Compu Anibuatory Research Contr Riverside Professional Building Dezarment of Paychony 66 2 ee So Mobo! Schoo! Minneapolis, MR SS484 Oftce: 612-627-4809 ‘Seis Pro ‘Aba Reseach Cee siese2 Mees M5554 onan shootd@ueme Seer Reich Corin ‘eaenz2gimacin ‘a Yate BLD, PD. July 30, 2008 Ms. Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 1528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455 Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cata~ ractogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPER- DAL) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Protocol 507711/0089, The CLEARS study. Human Subject’s Code Num- ber: Dear Ms. Webster, This correspondence is in response to your letter dated June 3, 2008, about the cataractogenic event and expiring study drug. I was unaware of the expiring study drug prior to sponsor notification because the drug does not contain the expiration date on the bottles, and information about this does not come with the shipping materials. 1 still do not believe that the expited drug caused any physical or psychiatric adverse events to subjects. ‘The letter to the subject with the possible cataractogenic event was resent via certified mailon 2008. The subject was not home when it was delivered and never re- tured to the post office to claim the letter, which was returned to me this week. T believe that we did everything we could to inform the subject of this event, and since the subject has not moved, it is likely that he received our original letter, which included a warning about not taking the medication in the future due to the risk of developing a cataract In other news, we have completed all subject visits for this study, and anticipate study close-out by the end of this year. Sincerely, Sel Olea Stephen C. Olson, M.D. Principal InvestigatorJune 3, 2008 Stephen C Olson Psychiatry Department F282/2A West-B 2450 Riverside Minneapolis, MN 55454 RE: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractogenic Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia or Schizoaffective Disorder Protocol 50771L/0089" IRB Code Number: 0310M53142 Dear Dr. Olson: Notification of IRB Committee Action IRB Meeting: May 28, 2008 Item Under Review: UPIRTSO IRB Action: Approval deferred pending receipt of additional information Additional Requirements Pending Approval: As the committee did not know the content of the letter sent to the subject or that the subject, received the letter, this unanticipated problem report had to be deferred. Please provide a written response to these points of concem: 1. The committee requires confirmation the letter has been received by the subject. If none exists, acquire said confirmation. 2. Since the committee does not know the content of the letter, confirm the subject has ‘been warned that he/she cannot take this drug in the future or risk developing a cataract. Ifnot, the subject must be aware of this fact 3, The committee noted the letter regarding the expiring drugs. Explain how the PI was not, aware of the expiring drugs before notification from the sponsor. The committee wants to remind the PI that it is the PI’s responsibility to identify and acknowledge unanticipated events and protocol deviations and act upon them in a timely fashion. If your response is not received within 90 days, the study may be filed inactive and a new application required for further consideration. Your response will be reviewed by the fall IRB committee. The IRB committee meets weekly; a list of meeting dates and deadlines can be found on the IRB’s Web site at http://www.rescarch.umn.cdu/irb/meetings/index.cfim,5924. Compliance Supervisor BS/pm CC: Donatd Doughman, Belle Khuu, Mary Lawrence, Elizabeth Lemke, Kimberly Snyder, John Vuchetich‘Committee Meeting Minutes May 28, 2008 ‘Agenda Item: UPIRTSO PI: Olson, Stephen ‘Reviewer; Schwarzenberg ‘Agenda Item: None Reviewer: None ‘Agenda Ttem: None Profocdl Title and HISCH: "A Multicenter, Open-label, Flexible the Cataractogenic Potential of Quetiapine Fuinarate (SERO! (RISPERDAL) in the Long- Treatment Up Pacha ‘with Disorder Protocol 50771L10089"" OS10MS3142 ‘the subject should b slo A letter: bei ‘sent ‘to th Diseussion of Controverted Issues Summary’ 5 [As the committee did not know the content of the letter sen rated problem report had to be deferred. ST | eer Please provide a written response to these pofits of concern: 1. The committee requires confirm has been received by the subject. If none exists, acquire said confirmation. 2. Since the committedlbes not ‘cannot take this drug i 3. Theor expiring drugs ‘econ events aud prote Petter, confirm the subject has been warned that he/she atarael, KE not, the subject must be aware ofthis fact . Explain how the PI was not aware of the responsibility to identify and acknowledge unanticipated imely fashion. ‘Gliaiige in RisidBen Non TRE Decision: Defer UPIRTSO ‘Additional Enfo: None Vote Yes: 7 Nao “Abstain: 0 Not Present: aD ‘Members Not Present for Vote Due to Conflet of li NoneADV 91: Olgon Study #0310"S3242 A Multicenter, Open-label, Fle Rev: Schwarzenbers/ “Meeting Date: 05/28/2008Consent Process _ 1, Does this a change it in the approved consent: form? Ns JPL has revised the consent formUNIVERSITY OF MINNESOTA “win Ces Comper Research Sabet’ Protection Programs Mayo Mat Cate 820 Instinuinal Review Board: Hanan Subjects Commie ins) 0.328 Maya Memorial fling March 6, 2008 tert es Catan Unc Comates (HCO 0 Deter Sie 3 Instant Boe Commitee (180) Mocenpads MN 59455 5 812.626 5054 Stephen C Olson 12.696 5654 Psychiatry Depariment®393 Teamete F282/2A West-B ‘acne un ada 2450 Riverside si ecachamneduebfcs mneapolis, MN 55454 RE: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractoge: Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia or Schizoaffective 50771L/0089" IRB Code Number: 0310M53142 Dear Dr. Olson: At its meeting on February 27, 2008 the IRB: Human Subjects Committee reviewed and noted the protocol deviation log for the referenced study covered by the letter dated February 1, 2008 which included a subject who had been taking Seroquel on QHS schedule as per standard practice to minimize daytime sedation ‘Thank you for keeping the IRB informed of the status of your research. ‘As Principal Investigator of this project, you are required by federal regulations to inform the IRB ‘of any proposed changes in your research that wil affect human subjects. Changes should not be initiated until written IRB approval is received. Unanticipated problems and adverse events should be reported to the IRB as they occur. Research projects are subject to continuing review and renewal. If you have any questions, cail the IRB office at 612-626-5654. Patrice Webster, CIP Assistant Director PWied CC: Donald Doughman, Belte Khuu, Mary Lawrence, Elizabeth Lemke, Kimberly Snyder, John Vuchetich Driven to Discover”Committee Meeting Minutes February 27, 2008 ‘Agenda Kem: UPIRTSO Pi: Olson, Stephen Reviewer! Crow if Agenda Item: None Reviewer: None Agendit Hem: None Submissi i Per a recent aite wouter vil rT salaie » prtoealiel fora ta that detals vo onsite devintions for IRB rogue by the letter dated mie subject had ‘There were no controverted issu evict, Clarifications or Supwlations: None ‘Change in Risk/Benefit Balanee: None TRE Decision: Accept ona) info: None [Not Present:apy Pi; 02808 BY ay wo2n0Ms3242 5 wolescenter Spen-label, ¥ on Rev: cxOw Ree: Cebace: 02/27/2008 ANY OF ENE re insti dose mene : Institutional Review B “ee jas the risk/t Elves. Ifyes.1 ee Subjects are:UNIVERSITY OF MINNESOTA : Olson | sZavee Nbimrenfe) OVOMSSIER rin Ces Campus Department of Pryehiary 282/24 West ‘Sehlopearia Progr ‘reir sare Cater (06 24m Avera South ‘uke one erat S454 ‘roreeer 4040 or2077 4008 sehicotrnis ek ‘Stephan Geen, MD, esto ‘Associ Professro Pephiahy eraaraores iscotoaturmsts lesbos Lamia, MA, COAG. ‘Soni Reesrn Coounatar erzezrase8 ‘aakso22Qurm.s ators Feesteh Coors reer aaa tn Yuet MD, PD. ‘Coinstar Petr Woe, MD, PRD. Cornvestgeor ‘.charas So, MD. Protec art oas Department Payehsty 2530 Riverside Avenue Minesapoli, MN 334541095 Office: 612272-9800 Mailed School May 6, 2008 Ms. Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Buil 420 Delaware St. SE ‘Minneapolis, MN 55455 Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPERDAL) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Protocol 5071/0089, The CLEARS study. Human Subjects Code Number: hy Dear Ms-Wébster, ? {am writing to inform you of a cataractogenic event for subject number that was found by one of the ophthalmologists on. , , 2007. As per protocol, subjects receive eye exams every 6 months during this 2-year study, and are examined by two ophthalmologists. During this eye exam, only one of the ophthalmologists identified that this was a cataractogenic event, while the other did not. This information normally would have been followed up at subsequent exams, but the subject dropped out of the study shortly thereafter and has not had any followup. We only recently were informed that because this was detected at the last available visit, it was considered a “cataract event” and due to sponsor error in notifying us in a timely manner that notification of the IRB was required. We have sent a letter to the patient to inform him of this, and suggested that if he is concerned about it to arrange for an eye exam. Please contact me with any further questions regarding this matter. Sincerely, Soe Hho Stephen C. Olson, M.D. Principal Investigator Driven to Discover”j “REE Olsen | s/ene NGA i UNIVERSITY OF MINNESOTA URIRTSON 2 — opiom saga vo oe Tacyinaneae paps Qegmeffoctory th ec ‘stipes Pern ry Rech Come 66 25cm St steer rors, ‘shops Seve Olan, MD, Dis eked Wud er ie, ED. PD. S Cave Sin, Pofee add Minnsapols, MOV 55056 May 5, 2008 Office: 6126274809 Ms. Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Building, 420 Delaware St. SE Minneapolis, MN 55455 Re: “A muhicenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL) and risperdone (RISPER- DAL) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Protocol 50771L/0089, The CLEARS study. Human Subject's Code Num- ber: Dear Ms, Webster, Attached is a Note to File listing expiring study drug that was dispensed to study subjects from 200710 2008. The sponsor did not inform our site of this expiring drug until” ~2008, and at that time subjects were given new study drug, Ido not believe that the expiring drug caused any physical or psychiatric adverse events to study subjects. Please contact me if you have any questions or concerns about this matter. Sincerely, ae Olson, M.D. Principal Investigator enelUNIVERSITY OF MINNESOTA rin Cities Campus Antbuatory Research Center Department of Peychiatry Medical Sehoo! Note to File Riverside Profession! Building {606 24h Avenue Son Sue 602 ‘Minmeapolis, MN 55454 Office: 612-627-4809 Listed below are expired study drug bottles that were dispensed and taken by study patients, ‘The study drug expired on 7/31/07 but the sponsor did not notify the site of the expiring drug until February of 2008. Batch # 87876 87875 87875 87875 87875 87875 87875 97875 87875 87875 87878 87878 87878 87878 87878 87878 87875 87875 87875 87875 87875 87875 ttle # Di 64693 7/3/2007 64876 7/10/2007 64981 8/1/2007 64571 9/5/2007 64689 6/26/2007 64691 7/24/2007 64578 8/24/2007 64596 9/26/2007 64983 11/26/2007 64673 12/19/2007 64281 6/26/2007 64304 7/24/2007 64287 6/24/2007 64302 9/26/2007 64289 11/26/2007 64285 42/19/2007 64600 7/30/2007 64572 8/28/2007 64573 9/26/2007 64982 10/26/2007 64874 11/30/2007 64984 1/30/2008 ensed_Returned ‘8/7/2007 ‘9/1/2007 91812007 10/1/2007 8/24/2007 3/24/2007 9/26/2007 116/208 1116/2008 4116/2008 8/24/2007 ‘9/24/2007 912672007 4716/2008 111672008, 1162008, 8/28/2007 ‘9/25/2007 10/26/2007 41/30/2007 12/21/2007 2n192008 Amount _# Taken 75 0 45 1 48 60 68 82 2 51 30 30 30 30 30 30 38 42 60 58 38 20SaaS ~SBayjo opis epueikce: ‘Syoaye opis jepuuetd: igo0zizs ~so0zisziy ~ soozrery ~sooreeiet 7B ple UORESKATUT\oujDOTe WIN —isoyoksd “TRBIGE Sapayeozyss Baw Aprys 0 oOue Byjo adAy) “dn mon spoday avs. suva1oJ9p108%p o16UKSA Jo Vor we apIOSIp On ‘Seed possaidop | SuOycAS zejod)a Jo BuUasiom ‘Oiksd jo Buen jSoupfsd jo Buuasom so0ziLir — ‘sooziezie SwiojdUUKS Jo Butuasiom +200) eprains (iej6dhg) stwO|duiKs Jo Buruosiom iiuone —rdwane apoins "dwege opraine ‘SO-AON-OE “uodey joaea spodey avs suvaToi ~Sooe/ezrel ~soozee'e t ‘go0ziezi8 _ gooeres go 02 ve [- gooeezi2t - ‘Biueu - — ‘900z/zi — eu C ‘o0z/iziet {eps Ieodia [- - Boozisir oo BIUEU TeI0d9 P - goozlezie — equew 00z/uzie ~ eueUi 1ej0diq, TT uodey jo e280 ‘aso dk po0etere a “p08 "/SS6URzp ‘deeds ‘ayeveuiny auidejend 229) uIse6 ‘dene eppirer, sduiene < suodey avs suvanoCLEARS. ‘SAE Reports Type of AE psychosis paroxysmal episode anemia, hypotension _ worsening of schizophrenia symtoms worsening of schizophrenia symtoms , depression hospitalization — ‘suicide attempt ton of schizophrenia nef Sehistatecive disorder onsen required ie hypertéision ‘bnermal ECS abnormal ECS Dale of Repar ‘4712006 -s/20r2008 “072008 5272006 ~ 6/27/2006 212008 10162008 “e2rra2006 9212006 10/5/2008. _weera007 —onf3005 "an@ra008 ‘52/2007Zo0eizeitr ZOOZIELIL S00z/Oeh 1 Sooe/Sz/LE ‘zoozioue zooziebie “20029219 ‘dooeizzre ‘Looziezre sooele s/t Zo0z/02/9 ~ 002149 20021916 ‘Looziere LO0ziewse Zoozhizis “00z16"8 “dooziezis |200zieis ‘200z/LUS Loozruis ‘oozizis Balap jadoe SeRpIeS swoiciks jo Buldasson 5 pois pu sapidsip 199 Jo Gujuesiom jepjoins pue iepicsip Uuonipuco Jo Buuesiom, L swoidiuks seI081¢ jo v0 0dKL, dn monioyn suodey avs swva10THOTT {pool posesaS “Fa ABT ue sep1099 nok) ees (peoul 1 ena | pur sopiosp anouokse) ‘sword wikS onoyak: ‘swojduiks SyoyoKSd J6" ‘S1SOUSAsd jo ui ‘suroidtifs SouoRss 76 ue sep.osip ayoussd) 2078/2 uo me}Aea jenuUe uoisUsisedKy ~wolst= och, SwoIdwiks SnoUDASd J6 uodeqiecexe ‘swoyduiks ajouaksd jo uoneqacexa sswordiufs Sy0yok8d 36 uonequacexa ~~ BeIsp (eides oe:p120 ~~ Worsueyedhy weubijew Budiinetid uohendse paxoadsns ~~ Sauepuadap loyooje “e2uspuadap auie900 jo asdejos ae 00g ‘UoReZIeydsou “yodayy jo 8186) By sO 2d syoday avg. suv3t0UNIVERSITY OF MINNESOTA Torin Cites Campns Ambsltory Research Center Department of Pychatry Madicet School July 8, 2008 Ms. Patrice Webster Executive Assistant, institutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Building exten £420 Delaware St. SE Sateen ome Minneapolie, MIN 55455 enol HN 8886 ‘Riverside Profesional Buleing 606 24th Avenue South Suite 602 Manneapoli, UN 3454 Oftce: 612-627-4809 Re: “A multicenter, open-label, flexible-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL™) and risperidone (RISPERDAL™) in the pana Jong-term treatment of subjects wit schizophrenia or schizoaffective disorder” “shige @umec Protocol 50771L/009, the CLEARS study. Human Subject's Code Number: Sete en MD, Dir Aenea ttsorttority Dear Ms. Webster, Attached is the safety reports log for the study cited above being submitted as a part of the Bisbehteme MA-CEES continuing review process for the 08/03/2007 to 09/24/2008 period. Please note, al ofthese enaree safety reports were reviewed by me and were judged to be non UPIRTSO. We will continue to keep the IRB inform of the study status as weil as any UPIRTSO related events. Please 2a er contact Belle Khuu or myself with any questions enemas ‘wh Sincerely, den Vas P,P. oo hv ‘S. Charles Sebut, M.D. Steph Olson, “Penfessor and lead Associate Professor of Psychiatry Depamrtiy ™ Director, Schizophrenia Program ex. 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A written IND safety report does not necessarily refleet 1 conclusion by the sponsor or FDA that the drug caused! or contributed to the reported adverse experience(s). If it is later determined the study drug caused the adverse event, this will be communicated yia an update of the Investigator’s Brochure. Please review the attached IND Safety Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethics Committee (URB/IEC) has received a copy of this, report for their review, per 21 CFR § 312.66. Please retain a copy of the written IND safety report as swell as documentation of the submission of this report to your Institutional Review Board/Independent Ethics Committee (IRB/IEC) in your study files. ‘ONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORT(S) MAY NOT BE DISCLOSED TO ANY PERSON OTHER THAN YOUR IRB/IEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR TRBMIEC. Please contact your study monitor with any additional questions and/or concerns you may have. Sincerely, AsuaZeneca Enelosure(s); IND safety report #3:AstraZeneca IND SAFETY REPORT DrStephen Olson University of Minnesota Dept. of Peyehianty 2450 Riverside Ave. F2822A West Minneapolis MN 55454 United States of America 7 December 2004 CONFIDENTIAL, Rez Seroquel, 50771L/0089 Dear Dr Stephen Olson, ‘The U.S. Food and Drug Administration (FDA) regulations require sponses of clinical studies conducted under a US IND to notify the FDA and all participating investigators of any serious and unexpected adverse experiences that may possibly be related to the drug under study, This is done by an IND safety report(s) which mny include a list of all safety reports conceming similar adverse experience(s) previously submitted to the same IND. ‘These reports may come from an investigational study, worldwide marketed use of a drug or published Jiterature and may include different patient populations than those included in your study. A written IND safety report does not necessarily reflect a conclusion by the sponsor or FDA that the drag eaused or contributed to the reported adverse experience(s). If t is later determined the study drag caused the adverse event, this will be communicated via an update of the Investigator’s Brochure, Please review the attached IND Safety Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethies Committee (IRB/IEC) has received a copy of this rroport for their review, per 21 CFR § 312.66. Please retain a copy of the written IND safety report a3 well as documentation of the submission of this report to your Institutional Review Board/independent Ethics Committee (IRB/IEC) in your study files. PLEASE NOTE THAT, CONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORTS) MAY NOT BE DISCLOSED TO ANY PERSON OTHER THAN YOUR IRB/IEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR IRBAEC. Please contact your study monitor with any additional questions and/or concems you may have. Sincerely, AstraZeneca Enclosure(s); IND safety report #s‘wauean, Apmis 01 payas.99 OLUEN® otn paLepISUOD JreBNSanKN aL ;pavonovo1 ak jou sey waned 24) “APIS a4] WOH UME:DURK Sem waned BIA pUe }90Z —_—_uo HanuqUEZSIp sem muaLANZa:AoMg, “aHQe} Aion pUE ‘povesed ‘paieybe ‘annaownbve ‘SuuaTe0. Aeqion Sem iuaned aun ‘uossUpe jo Kep au ug) waned axa Kq pavan ey snow si eadsoy aun < uo pur ‘pauasiom swords si aIgeoup-21 SEM Ing Jo surrduuks padorenep ay “yo02- ounksd Jo Loneqyeaexa auones poovaUedko PUP 4002 uv Brip Apmis weBag waged au uo panes wary ‘uoney6e 40) wedazeso} pur "UOSUI20} uatydouruierane popnjaul sGiup eywODUED eyOWS € Ost Sia} ‘Avorapuedde pue ‘odoouXs ‘asnge (7 ue ‘euleo09 ‘wOsEW uve 'g sanede4 ‘uotednsuoD Suox Jo Kas ep Walled 24 ‘auanidoziog yam siuaneg i Kemnay Jo waUse=s) ut UF ogaDe%d But tun auxierant) uoneinuioJ aseamy-Pauesns jo Mayes pus Aoeow3 aiM JO uOsUEdWO? PEzMuOpURY "sULIND ‘ng ‘BUA-e}aROg YAIUBTHNWY ABMS Y ~EELOOONHNEC APMIS UI oYOMD waned ayoul Buwseau09 JoweBisonut ue woy pariaves sem uode! y op enneney asegZ NVALLY ‘NII TONTTAL | {6)BruqaueMWosUED wueASteR) 1(6)6rug aedsng seg vandouas | __:Aoms sepun Brug eoouszensy 602-936-913 ‘LYOGRY ALAIVS 9569 GNI‘pumas sose9 pomnuigns Aisnornaid oN Sar IS is] Riewong VSS By mig iopuT woneGUT gay 2¥G3 41 01 poRGNs AIsnomadg SjueNg asuenpY pareray Aiqissog ‘paroadxaun ‘snouag se} UNS Jo Bunsty *¢ "ne po 2qoUUeD Grup Anas Bue Sos JSuoneRsenexe Loamag dysvoneiaqesneD Y :weWLHO>) emUND Avedue? op anneney aseg 2 2218 0686 39 woo, SLVUYINEANIaYLAND pris sopun Brug eoouszensy “remereaty nin ea wor o09 80 18OdTY ALRIVS 9893 GN Searenney ibyDr Stephen Olson University of Minnesota Dept. of Psychiarary 2450 Riverside Ave. F282/2A West Minneapolis MN 55454 United States of America 13 December 2004 CONFIDENTIAL Rez Seroquel, 507711 /0089 Dear Dr Stephen Olson, ‘The U.S, Food and Drug Administration (FDA) regulations require sponsors of clinical studies conducted under a US IND to notify the FDA and all participating investigators of any serious and unexpected auverse experiences that may possibly be related to the drug under study, This is done by an IND safety report(s) which may inclide a list of all safety reports conceming similar adverse experience(s) previously submitted to the same IND. These reports may come from an investigational study, worldwide marketed use of a drug or published literatare and may include different patient populations than those included in your study. A written IND. safety report does not necessarily reflect a conclusion by the sponsor or FDA. that the drug caused or contributed to the reported adverse experience(s). If'it is later determined the study drug caused the adverse event, this will be communicated via an update of the investigator's Brochure, Please review the attached IND Safety Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethics Committee (IRB/IEC) has received a copy of this report for their review, per 21 CFR § 312,66, Please retzin a copy of the written IND safety report as well as documentation of the submission of this report to your Institutional Review Board/Independent Ethies Committee (IRB/IEC) in your study files. PLEASE NOTE THAT, CONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORT(S) MAY NOT BE DISCLOSED TO ANY PERSON OTHER THAN YOUR IRB/IEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR IRBAEC. Please contact your study monitor with any additional questions and/or concemns you may have. Sincerely, AstraZeneca Enclosure(s); IND safery report #°Sem WOKS aU "POOR. 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EOS UR] KaIoagSvs SOY Toms pun ona, F eON UR a4 aun 61 penjwang AisnojAaig siuong ssieApY paretey Alglsseg ‘payoadxeup ‘snouas seyWWIS Jo BuSTT s ‘syoaya 2u} 0} juo9 ayexeuiny suldenend 1eup s9naMoy papnjoxe eq youUeD y JOYoOYe Jo Spa's Buisseidep-GNO UMOLY, yen 21g 6uyap|sucd ‘jouoore pu syereun auideyanb fo ayequ paUqUIOD alo} ajREINauNE Aen! S WANE 84a 'SNO SHoeye yesy eyevewy euennb YOnoE ‘vanamho} uene at pu OUoDe puE eeLeUIT sudeend Jo ayeqU! peuIquod ax usaMaN diysuORefe! uN eyqeUOSee: e S aOU) qWAUINOD Fea AuedUIDD J4ooye pue ejexeuin aurdeyenb jo uose6u oU7 0 payyeu AesTeO WaNe &y pazepIsuoD JeOSeAUL SUL “Apnys au u] panuquoo uayed 9x ep xeu eu) uo Bejanbas inoqum palenooas uaned euy “juEodwy ApeaIpaL, Hoy eANeIEN 9829 2 dey 4 SUVUWWNS BNIdvILEND :Apnys sepup| Brg edavezensy sae ony ANOdRY ALBIVS ZE1'ZE GNI SHeUNeDeWg eUAZEISYAstraZene & Dr Stephen Olson University of Minnesota Dept. of Psychiariry 2450 Riverside Ave F282/2A West Minneapolis MN 55454 United States of America 12 August 2005 CONFIDENTIAL, Rez Seroquel, 50771L/0089 Dear Dr Stephen Olson, “The U.S. Food and Drig Adminstration (FDA) regulations require sponsors of clinical studies conducted under a US IND to notify the FDA and all participating investigators of any scrious and unexpected adverse experiences that may possibly be related to the drug under study. This is done by an IND safety repori(s) which may include a list of all safety reports conceming similar adverse experience(s) previously submitted to the same IND. “These reports may come from an investigational study, worldwide marketed use of a drug or published Jicerature and may include different patient populations than those included in your sudy. A written IND safety report does not necessarily reflect a conclusion by the sponsor or FDA that the drug eaused ‘or contributed to the reported adverse experience(s). If itis later determined the study drug caused ‘the adverse event, this will he communicated via an update of the Investigator’s Brochure. Please review the attached IND Safety Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethics Committee (IRB/IEC) lias received a copy of this report for their review, per 21 CPR § 312.66. Please retain a copy of the written IND safety report as well as documentation of the submission of this report to your Institutional Review Board/Independent Ethics Committee (IRB/IEC) in your study files. PLEASE NOTE THAT, CONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL, STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORT(S) MAY NOT BE DISCLOSED TO ANY PERSON OTHER THAN YOUR IRB/IEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR IRB/EC. Please contact your study monitor with any additional questions and/or concems you may have. Sincerely, AstraZeneca Enclosure(s); IND safety report #'s:zp ees ‘oqereuny eudenonb ym Aderay op 21 Aesned wena 219 paseprsuon oR BASOA SYL “pode: sig yo fun expe pasanooar ef jou pey waned eu ‘ep/dus y wedazeuoe im payean sem teged aU ‘ons 2p ParunUEDsip yuaned aug pue paddoys sem LORIE fonig'sone wo pesreyds0y sem uated eu Yjasuty aUBIeANY Ose Wayed sly, “JepI0s!p WGnow svenas yum sIsoUaKSd peouavadke waned au'cooz vo"ajeseuy audeyanb yu ueuuzean Buneys oye syucw om Kaieworddy (Code uooxnuednp pue cone uo-surzeedonys) panujucosip sem eydozives Jo} uoqecipew snovnatd aul, ‘soce uo (fyeso ‘But 09g 8800 Ayep}aievewny ouidenenb Srup Apmis veBaq WeRed Su, ‘ons sy) so4 Aefins auofepun pey pve (seinjey adam) Ani peau jo fuoIsy @ pey waned sus, canannos in suaged ua (erboi9g) ‘sTesewn, auidegend oseajai-pauieysns 0} weunean sgouKsdyue Aue Guyowms Jo ‘Ampaysee) 24q syenyene 0} Apmis anqeredwco-uou “jage] uado “sequent ‘youoweWieq yeeN-Z) © “Zp}00breL APMIS UI peyowe yaRed UEISEINED eye Suwseouoo soeBasenun Ue WOH penleoed Sem Loder Joy aneueNy 25e9 "2 q wweyuoouog weRBIEY | joodsng 00 ‘ranoouss | Apmis sepun Brug eseuezensy | Ja] Krevonaig) we peyoday (s)ays peroedxoun | 01 Keung) we psyodeu (Slavs Pope 30 Axjunog, STH 2xag | ro8y | [oma anion yo} Kiewung ase" eeproassodz :# dou at ALVUVIINS 2NIdVILAND _:Apmig Jepun Brag eoeuezensy saneon¥44 a0 MOdTY ALBIVS 959'99 GNIpunoy sas pamrurgns spenorard oN. Ba INS WR MRIS S OS ay Fig epuN woRROpUT CONAN 2¥Cd 84) 0} palwang Asnonaig squang esrOApY PaTEfey Ajqyssod ‘payadxaun ‘sno|0g seIWNS Jo BUNST "E ‘oras sopun aesosip 24 suogerany 'B o} an paLinaco yuan sup yeuy ANNES weyduoo-uou Busq waned eu ‘szesp punasoeq suoyed ot jo Buosion Las aygeuosee!e sau “aN, nidogns (} -ssoyo2 Bucy; 8 Jo uogeutqUoD jou S1 sBoupAsy ‘veiuWog [eoiung Auedwog issodas0p Guow) But jenend 10} SQ aud HO} @ANEMIEN 9829 % sre 20 nt BIVEVHNd ANI¢VILAND _:fomis sapun Brug eosuezeNsy “Soames somonvit 0 ‘gEDaURZeIY PRN SSNS AMOS ALBIS 959'S7 GNI ‘genmneoewueig PoevazEIEyDr Stephen Olson University of Minnesota Dopt of Psyehiartry 2450 Riverside Ave. F2822A West ‘Minneapolis MN 55454 United States of America 25 August 2005 ‘CONFIDENTIAL Re: Seroquel, 5071/0089 Dear Dr Stephen Olson, ‘The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies conducted ‘under a US IND to notify the FDA and all participating investigators of any serious and unexpected adverse experiences that may possibly be related to the drug under study. This is clone by an IND safety reports) which may include a list of all safety reports concerning similar adverse experience(s) previously submitted to the same IND. “These reports may come from an investigational study, worldwide marketed use of a drug or published literature and may include different patient populations than those included in your stady. A written IND safety report does not necessarily reflect a conclusion by the sponsor or FDA that the drug caused ‘or contributed to the reported adverse experience(s). IF itis later determined the study drug eaused the adverse event, this will be communicated via an update of the Investigator’s Brochure. Please review the attached IND Safety Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethics Committee (TRB/IEC) has received a copy of this report for their review, per 21 CER § 312.66. Please retain a copy of the written IND safety report ax well as documentation of the submission of this report to your Institutional Review Board/independent Ethics Committee (IRB/IEC) in your study files. PLEASE NOTE THAT, CONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL, STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORT(S) MAY NOT BE DISCLOSED TO ‘ANY PERSON OTHER THAN YOUR IRBAEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR IRBABC. Please contact your study monitor with any additional questions and/or concems you may have. Sincerely, ‘AstraZeneca Enclosure(s); IND safety report #’s:sysauneen yo vouesseo vo fusaras se1e0%6 yam paumas Keun aunaum pue sworduks axa BurpreSe) LoneuHO}UL 3 auouog feat Kuedior ‘qeqene ov s1 o2uapi 1uo!yns se uoneDjpaLs Koms oy pareexLN wane Siep|sucD MoU URDISKyd Mayes Brug 7y Odes peIseH0D nunu09 som jonbotag wnowyun spe unowyn si oapuoD sented OL eonBeTEESEL xen shoves polepsuco ava (sjsone au (fous) LncUUN UR Joye) SUES oHOUDKSE asker pooueHadx@ puE Grup Apms weBoG ened au] ‘audezop papninua sBrup wemwooue) eupnydoztes uoieyos eudez0;9 wy eurderond Samer (EZOS0OLHPLO) €Z06IL105 Kors wy payowe weRed e Buweauo9 srefusarul ue Woy paNanes Sem Vode! Y HOP OAReMEN 2529 °Z ~ 3Mev2070 (Brag wiewO9u0D WeNAON | ~~ t {Brug woedsng s01N9 | ~ ypauneg IID ~ 1 1 fueduoy 205 shyesnen Kuedwog | pevot=yoq sfyesneg soreBnsony | janooszs | -APmg sopup Brug eoouezensy | _ 1 sigson -Rmweapy sneneg | SONVTISHIGN abu Rnane | woe 9g wn eby Leaniorios :odk uodey | aoros sjuoneoiey | ‘oN 10901014 suo} Aueunung 2569 "L 05961 30 vain, | ALVAVEINS Navan :Apmis sopup Snug eoouszensy | ‘saceoneee ae LYOdTY ALIIVS ZEL'ZE ONEAstrazeneco? _ IND SAFETY REPORT Dr Stephen Olson University of Minnesota Dept of Peyehiavtry 2450 Riverside Ave. F282/2A West Minneapolis MN 55454 United States of America 24 August 2005 CONFIDENTIAL Ret Seroquel, 50771L/0089 Dear Dr Stephen Olson, ‘The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies conducted under a US IND to notify the FDA and all participating investigators of any serious and unexpected adverse experiences that may possibly be related to the drug under study. "This is done by an IND safety report(s) which may inchide a list of all safety reports concerning similar adverse experience(s) previously submitted to the same IND. “These reports may come from an investigational study, worldwide marketed use of a drug or published literature and may include different patient populations than those included in your study. A written IND safety report does not necessarily reflect a conclusion by the sponsor or FDA that the drug caused ‘or contributed to the reported adverse experience(s). If itis later determined the study drug caused the adverse event, this will be communicated via an update of the Investigator’s Brochure. Please review the attached IND Safety Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethics Committee (IRB/IEC) has received a copy of this report for their review, per 21 CFR § 312.66. Please retain a copy of the written IND safety report as well as documentation of the submission of this report to your Institutional Review Board/Independent Ethics Committee (IRB/IEC) in your study files. PLEASE NOTE THAT, CONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL, STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORT(S) MAY NOT BE DISCLOSED TO ANY PERSON OTHER THAN YOUR IRB/IEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR, IRBIIEC, Please contact your study monitor with any additional questions and/or concems you may have. Sincerely, AstraZeneca Enclosure(s}: IND safety report #zp 1 ate qwoungan yo uonesco9 Uo Kanes J2}2016 uw pawsrna ay oepauys pu suIOwdufs eur BuIA! UONeWHO; WaLaYNS eUNOD feaRALD uedwog ‘Kdesau fas 01p 02 peas Kyesre (shore aug paxopisuos uerrsfug Keses Brug eaav0z pan sn jonboveg jrumoUyun sy ue umOLRUN Ss) uoRIpUED S waned au "Uh ©; anp snouas paxepsves a:om (sjuone ayy. (Kousre wioun Ue ) swiordusts spowoksd aszenou poousuede pue Grup Apmis uebIeq 1 ‘oudezops papnpur sBinyp weawonu0 ‘ibaaidoangs Aropeip3 audezao us sudenenb Bune (EZ06N0LPFLG) EZOBILLOS Fons uw paIORD toned 2 Gueouoo sowebjisoN Ue Woy pan|oDD! Sem Lodas y 140} aneney asey"Z TavZOTD | __A)Brag weamieauey wensIey -(9)8muq wedsns 101 "WAIN IUD fuesuon 9g :Aypesneg Auedwog | —psvodeaj1oN yesmeg soreBins ant ianvowss | __ Anis sepun Grug essus7ensy (Wepies snouts) swcndang ounksg asa (ua Krevoncig) wey pevoday (s)a¥s parsadxoun, NOUNZITldSOH (EpeWwPUY snows | —_SONVRISKIN *UGUQ yo Anunog | unomun aS wv 8y Twin 00K, wodoy, euaulcains —x{S)uORe=pH FON 10001054 uo Krewung 9829 °L Leys 59 30 wenn 18¥81 308 ‘04 td ROIED ONAL ALWEWWNS INIGVIL3ND _:APms sepun Grug esouszensy seer onve2 20 180434 ALBAYS ZEL'ZE GNIcRuaOoM z ~ I ‘Gs3NOOE W - auandae moon 3S xs aay (BRIS SUF] BORE: Fe VQ 2th 01 pannuan Kisnomaig siueng ostonpy pereioy Kiaissod ‘paroedxeun ‘snoueg seg Jo BUNStT's ‘doy “at BLVUWINS INIGVLLIND :4Pms sepup Brug esauezeasy sooeonwez #0 LNOdIY ALBIVS 261'2E GNi UNIVERSITY OF MINNESOTA February 04, 2005 esearch Shee? Protection Programs Mayo Mait Code 20 @ tao) D328 Mayo Memorial Bulding Inetatone Review Board: Human Subjects Commie tka) 2228 Mayo Meneria 8 stephen C. Olson Ina nial Cre and Ue Comme Cue) "420 einer Ser Psychiatry Department Facer? 6266061 F2822A West-B so annedt 2450 Riverside exGun Minneapolis MN 55454 wee Re: "A Multicenter, Open-label, Flexible-dose, Parallel-group Evaluation of the Cataractogenic Potential of Quetiapine Fumarate (SEROQUEL) and Risperdone (RISPERDAL) in the Long-term Treatment of Patients with Schizophrenia or Schizoaffective Disorder Protocol 507711 /0089" Human Subjects Code Number: Dear Dr. Olson: Atits meeting on February 2, 2005 the IRB: Human Subjects Committee reviewed and noted ‘unanticipated problem and adverse event reports for the referenced study. The following reports were included in this review: . ‘Initial dated December 6, 2004 . Initial dated December 16, 2004 ° Follow-up dated December 10, 2004 ‘Thank you for keeping the IRB informed of the status of your research. As Principal Investigator of this project, you arc required by federal regulations to inform the IRB of any proposed changes in your research that will affect human subjects. Changes should not be initiated until written IRB approval is received. Unanticipated problems and adverse events should be reported to the IRB as they occur. Research projects are subject to continuing review and renewal. Ifyou have any questions, call the IRB offfice at (612) 626-5654. Sincerely, 4X (ive. WWF Patrice Webster Executive Assistant PWied CC: Donald Doughtan, Jean Kenney, Mary Lawrence, Elizabeth Lemke, Sellmann Schulz, John ‘VuchetichADV PI: Olson Code ¥:" 0310Ns3z02 A Multiconter, Open-label, 1 Rev: Luke Meeting Date: 02/02/2005"Stipulations must be met by the investigator before the study is formally reviewed for approval. __ Suggestions are relayed tothe investigator but do not need to be complied with for the study to be approved. pate: 20S+ OLE we Mee OL UNIVERSITY OF MINNESOTA OF (CMS2 | Ambulatory Research Center Department of Psychiatry Riverside Profesional Building {606-24th Avenue South Meéical School 5-24 “Mizneapli, MR S5454 December 28, 2004 ‘Ms. Patrice Webster Excoutive Assistant, Institutional Review Board University of Minnesota MMC 820 1528 Mayo Memorial Building 420 Delaware St. SE, Minneapolis, MN 55455 Re: “A Multicenter, open-label, flexibie-dose, parallel-group evaluation of the cataractogenic potential of quetiapine fumarate (SEROQUEL™) and risperidone (RESPERDAL ™) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Human Subjects Code Number: Dear Ms. Webster, Enclosed please find in this letter are the following off-site IND Saftey Reports: © Case Summary nitial) © Case Summary (Follow-up #1) © Case Summary (iia!) Please direct any questions about this amendment to myself (612-273-9763) or Elizabeth Lemke (612- 627-4364). Sincerely, ) Stephen &. Olson, M.D. Principal Investigator enc.Dr Stephen Olson University of Minnesota Dept. of Peychiariry 2450 Riverside Ave, F2822A West inneapolis MN $5454 United States of America 17 December 2004 CONFIDENTIAL, Ay Ret Seroquel, S0771L/0089 \ Dear Dr Stephen Olson, ‘The U.S, Food and Drug Administration (HDA) regulations require sponsors of clinical studies conducted under a US IND to notify the FDA and all panicipating investigators of any serious and unexpected adverse experiences that may possibly be related to the drug under study, ‘Ths is done by an IND safety eport(s) which may include a list of all safety reports concerning similar adverse expetience(s) previously submitted tothe same IND. ‘These reports may come from an investigational study, worldwide marketed use of a drug or published literature and may include different patient populations than those included in your study. A written IND safety report does not necessarily reflect a conclusion by the sponsor or FDA that the drug caused or contributed to the reported adverse experience(s), Ifitis later determined the study drug eaused ‘the adverse event, this will be communicated via an update of the Investigator's Brochure. Please review the attached IND Safely Report(s). You are obligated to ensure that your Institutional Review Board/Independent Ethics Committee (IRB/IEC) has received a copy of this report for their review, per 21 CER § 312.66. Please retain a copy of the written IND safety report as well as documentation of the submission of this report to your Insittional Review Boare/ndependent Ethies Committee (IRB/IEC) in your study files PLEASE NOTE THAT, CONSISTENT WITH THE CONFIDENTIALITY PROVISIONS OF YOUR CLINICAL ‘STUDY AGREEMENT, THIS LETTER AND THE ATTACHED REPORT(S) MAY NOT BE DISCLOSED TO ANY PERSON OTHER THAN YOUR IRB/IEC AND MUST BE KEPT CONFIDENTIAL BY YOU AND YOUR IRBAEC, Please contact your study monitor with any additional questions and/or concerns you may have, Sincerely, AstraZeneca Enclosure(s): IND safety report #'s:cm abeg 9p paqusosd JoU| ue axoW Buyer KyevoReN! 0} pene ays Se esopsaRD UOHED!PAL PUE UONeED! lepIns 10 Knaus paused aus ‘sae| SAMUI rewxoxidy ‘paquasaid se usu JaLpes acuo Ye janboras, 4g 'S2s0p pepmp ut Ayepj6us qgt ‘auxtenenb foqet-Uodo jo asp e10 ue uo eBeg waned ay 'yOQZs ——_j UG lorem pue 2904 1464 Jo snasjuau wo) ‘eusoz99 “eILNsU ‘souepeaL IM SIS0%D9U JIB ‘SSeOSID Jo|NISNA yerouduad eiMIUED YIM eNaLE ssaxdap Buuas.on ‘sieeK usar ut Burs uorssestan jo Kio e pey wiened ay ‘puey 1611 40 scruBBuy snoy yo uc ‘unuyoine “asn ouWwerouRweYTaU ‘asopuaro snowed 'SIBeK > 18219 us 4Bten 20) suusaIUaud pure sazHgeIs poow 49} 92? ed Ba 0} 200K pee Uyak “eaLE 20] UOR PooMUISBrUP WuEHOE? stvoneg InpY Uap.0sig | s3}08g 01 Dunfpy se posh uayjy oqa2etg ot areewn4 auiderend Jo Kozes nue Kre2y3 waned 329) Buusoou0o mrebnson uP Woy panna! sem oda y 4 oj aaneey seg 2 a INMRIBINSH FQY OWTA'N3 AORN NOW {5)Brug ae WoDUOD ERE 2(6)6rug 1oedsng soyig owt ee Fumduiog 205 shypaneg huedito3—paeey fase) Kuesneg soreSnsonuy Tanbouss——_-Aemis spun Bug eoauozensy SON, (6rltshg Baume pamusvag | x(a94 fsevoreg) unoy oauodoy (¢)ays peroedxeu HoUaIMNeSOH ay posi poN-KON-O| UO BoBUEZeUISy hq paNa794 UO! payers ojos jo Ksewng soprano, nowy -papwod! Kons Guprebes uoyer uonoy “powepdh Assy amen :}002-dog-L1 eoeueeNsy fa BanlaTa! UAL ‘dos pms 01 paeres 2q 0% Buyer) papuisuos passesse voreGaconuy “Adeaun foris ain 01 potelun aq a1 asopIeNO Jo wlAKS 2xp parepIsueD LoVeGnSSAU! aU "SEI waned ay, “sn Jezo4y aruMUOD HH pue yerdSOY aiN WOH PABIEUDSD Sem US “POD ug. uASSeIdeD 0 Uo pau sem ous paayeudsay any ‘PaXosas DasopIsuOD Sem wBAA a Lg Pavodss oste som gg 50 9s0: od sem powuoyad uodIs Aipxo: y “ARE am subs jeNy PaIUaHO Hue Uae "URSEON! Se paNUNSaP Sem BUS LOSSHUDE UD “seLILReUdUE Ho) aaneMeN aseg "2 LIVIN INIGVILAND _ :Apms spun Brag essuazensy oz 930 0-9 AMOS ALIS 2212 GNIemt obey A semr> pangs Ksnoinaid oN Tips pu woR=py— FTE ‘Wa eH 01 pontuans Asrowezy swing ostonpy perrey Kaissog ‘potoedxaun,‘shoLeS seNUNS yo BUNS ¢ BRNO TS ‘aia TRUONG IVS aS ay ALVUVIINS 3NIavLIND emg s9pun brug esouszensy 002-330-096 TYOdRY MAIVS 281'ZE ONEUNIVERSITY OF MINNESOTA saris Resear Corer Degarinent of Peehiairy ‘Riverside Profesional Bling Medica Schoot 62a avert Soth ‘Minmenplis, M0 55454 August 31, 2005 Ms. Patrice Webster Executive Assistant, Institutional Review Board University of Minnesota MMC 820 D528 Mayo Memorial Building 420 Delaware St. SE Minneapolis, MN 55455 Re: “A Multicenter, open-label, flexible-lose, parallel-group evaluation of the cataractogenic potential of ‘quetiapine fumarate (SEROQUEL™) and risperidone (RESPERDAL ™) in the long-term treatment of patients with schizophrenia or schizoaffective disorder” Human Subjects Code Number: 0310MS53142 Dear Ms. Webster, Enclosed please find in this letter are the following off-site IND Safety Reports: Please direct any questions about this amendment to myself (612-273-9763) or Elizabeth Lemke (612- 627-4364). Sincerely, Stepheh C. Olfon, MD. Principal Investigator encl.

CLEARS Study SAE Reports by Stephen Olson

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