Word 41) ed ABE Del ympth KING'S fon bei rat tit boos bk tie ‘an Academic Heath Seances Cates for London Pioneering better heath forall King’s Health Partners Clinical Trials Office Pharmacovigilance & Sé Reporting Polic Dosunent Tipe Operate Poey Document name Pharmacoviglance & Safely Reporting Version Fina 1 26 Speer 2018 eects fom 7 Sotomter 2016 Fev date 2 Soto 2020 ‘Owner King’s Heath Parirs Cinical Tals Ofice Oral Pepered by Jace ud Gut Harogor Fovowed by Helen Ge, Quay banger ‘Approved by | seco Pillen, Director KHECTO | Sipereoded camer Pfarmacovlanc Stay Reporting 7.008 Dec fare Relevant | Statutory instrument 2004 no 1091 - ‘regulations/egisiation/guidelines | srat,tory Instrument 2006 no 1928 Date | Version| ‘Change details ‘Approved by Number ove2r00e | 40 Jacki Powel 1270272008 | 2.0 _| Addition of Pregnancy Safety Reporting. | Jacke Powell s1voe010 | 30 | Change in MHRA pocy to eSUSAR “Jacke Powel reporting, clarification of unblinding & downgrading of Pl reports by CL ‘Transfer to King's Health Partner Livery. sainazo11 | 4.0 | Amendment of ASR to DSUR as per ICH | Jackie Powell 2 guidance, | 2Sep2018 FINAL v4 Page 1010Date Version Number ‘Change details “Approved by sorror012 50 Change of branding to KHP-CTO and update to include reporting of Important Mecca Events" Jackie Powel stn 60 ‘Minor clarifications to reporting procedure Jackie Powel oenane 70 Update of Glossary and seheduled review. Update of MHRA contact Information for Urgent Safety Measures Carfcation that folow up safety data may be collected from ur-binded Paticipants ‘Jackie Palen 6104/16 20 Update of ext to lay reporting process for SUSAR, Important Medical Event correlates to "Other Medically Important Conlon” for {°SUSAR reporting and the use of MedORA terminology should be used to code eSUSAR events. Inclusion of MedORA in the glossary. Jackie Pullen | 2610972018 a4 Minoeamendment to incude tials ‘managed by KHP-CTO are covered by this SOP, “Jackie Puen 287Sep2018 FINAL V6.4 Page 20610GLossaRy ‘Adverse Drug Reaction (ADR) - Any untoward and unintended fesponse in a subject to an Investigational medicinal product which is related fo any dose administered to that subject. ‘Adverse Event (AE) - Any untoward medical occurrencalin a sUbect to whom medicinal product has been administered, incuding occurences which are nat necessary csused by or Felated to that product Chief investigator (Ci) - A Registered Physician, Dentist) Pharmacist or Registered Nurse ‘who has overall esponsibility forthe conduct ofthe til, Clinical Trial» Any investigation in humen eubjeets| other than = nonintervertional trial Intended to discover or very the clinical, pharmacological andlor other pharmacodynamic. ‘effects of one or more medicinal product andor to ident any adverse reactions to ane oF more such products andlor to study absorption, distribution, metabolism and exertion of one ‘or more such products with the object of ascertaining the safety andlor eficacy Data Lock Point - Day prior tothe DIED. The Sponsor can designate this asthe ast day of the month prior to the month ofthe DIBD. Development International Birth Date (DIBD) — Date ofthe frst authorisation to conduct a inal tal of a spect investigatonal medicinal product in any county wodawde, Development Safety Update Report (DSUR) - A common standard for period reporting on rugs under development (inludin marketed druge that are under further study) among the ICH regions, Inthe EU replaces the annua saety report. King's Health Partners. Kirg's Health Partners Academic Health Sciences Centre Is a Pioneering colaboration between one ofthe King's Colege London (Universit) and three of Condon's most successtur NHS Foundation Trusts ~ Guys @ St Thomas, King’s College Hospital and the South London & Maudsley. King's Health Pattners Clinical Trials Office (KHP-CTO) - Established in 2006 by King's College London, Guy's & St Thomas’ NHS Foundation Trust, South London and Maudsley [NHS Foundation Trust and King's Cologe Hospital Foundation Trust o provide a sreamined approach for all aspects of tial administration Important Medical Event (IME) ~ Events that may not be Immediately ifethreatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed inthe definition above should also be considered Serious. For the purposes of eSUSAR reports, IME corralaias to the ICH Topic £28 crteia “ether medicaly important condition” 2v5ep2018 FINAL v8 Pago 10Medicines & Healtheare products Regulatory Agency (MHRA) - UK Competent Authority ‘responsible for regulation of cinical ils, Medical Dictionary for Regulatory Activities (MedDRA)- AV clinically validated Intemational medical terminology cetonary (and thesaurus) used by repulatory thoes for ‘the purposes of adverse event clasaieation, Principal Investigator (Pl) - A Registered Physician, Dentist, Pharmacist or Registered Nurse who has responsiblity forthe conduct of the tral et a host site. Quality Policy - Policy signed bythe Medical Directors of the Partner Organisations and the Vice Principal of the Health Schools of King's College London. The Quilty Poley binds all relevant cinical research actviy conducted or managed by the Partner Organsstions to the KHP-CTO Clinical Tia SOPs, Research Ethics Committee (REC) ~ An independent body in a Member State consisting of healthcare professionals and non-medical mambots, whose responabilty Isto protect the "ights, safety and wel-being of human subjects involved in a tial and to provide puble ‘assurance of that protection by, among other things, expressing an opinion on the til Protocol. the suitably ofthe investigators and the adequacy of facts, and onthe methods land documents to be used to inform tral subjects and obtain thee informed consent. ‘Serious Adverse Event or Reaction (SAE/SAR) -A serious adverse event i defined as an ‘adverse experience that results in ary ef the following outcomes: + death ‘+ alfestweatening adverse experience (any adverse experience that places the patiot ‘or subject, inthe view ofthe investigator, ct immediato isk of dath from the reaction as occured, ie, it doesnot include a reaction tha, had occurred Ina more severe form, might have caused death) + inpatient hospitalisation or prolongation of existing hosptalzation + 8 persistent or significant aisabiltyincapacty (a substantial disruption of a person's ably to conduct normal ite functions) +a congenital anomaly/oirth defect ‘Sponsor - The organisation who takes responsibilty forthe nition, management and financing (or arranging th financing) in relation to a cinial trial The Sponsor organisation has responsiity fer errying out the Sponsor functions ofthat tal (as defined in the Regulations) ‘Suspected Unexpected Serious Adverse Reaction (SUSAR) ~ A Suspected Unexpected Serious Adverse Reaction is a serious adverse drug reaction, the nature and saver of \which is not consistent withthe information about the medicinal product in question set out ‘inthe case of a product with @ marketing authorisation, in the summary of product characteristics for that product. + “inthe case of any other investigational medicinal product, in the invetigato’s brochure relating tote tal in question ‘The Regulations - Statutory Instrument 2004/1031 — the Medicines for Human Use (Clinical ‘iials) Regulations 2004 which transposed the European Union Divecve 2001/201EC for 286972010 FNAL We 4 Page 40110CGnical Trials into UK law effective fom the 1 May 2004 and any amefiéns that may Unexpected Advorse Drug Reaction - An adverse drug reaction the halve and severity of ‘which isnot consistent with the information about the medicinal product in question set out ‘+ inthe case of product with a marketing authorization, inthe summary of product ‘characteristics for thal product, ‘inthe case of any other investigational medicinal product, in the investigator's ‘brochure relating to the trial in question, BACKGROUND AND PURPOSE “The Medicines for Human Use (Ciical Trials) Regulations 2004 set cut specific requirements for the management of serious adverse events (SAE). Of particular importance is the ‘ascessment of any event for cauealty and expactodhess. [AEs that are.not considered serious should be incled on the relevant case report forms (CRFS) as defined in the val Protocol. This data wil be included in the final ial rerort. ‘SAEs can be classified into diferent categories: + Serious Adverse EventReaction (SAE/SAR) + Suspacted Unexpected Serious Adverse Reaction (SUSAR) Each type of SAE is subject to diferent reporting requirements. tis vital that this Policy is followed as failure to report Incidents, or deal wih incidents adequate, can have the Potential to jeopardise the safely and wol-being of tral subjects. This can resut in regulatory Approval being withdrawn from an individual project, o, in extreme cases, from all research Carried out by the Chief Investigator (Ci) er Principal investigator (Pl), ‘There area numberof resporsibities when managing serious adverse events. Below is ist ‘of responsibil for bath the Investigator and the Sponsor SCOPE All clinical Wale involing Investigational Medicinal Products (IMP): a¢ defied in the [Meicines fr Human Use (Clinical Trials) Regulations 2004 (as amended fom ime to time), ‘sponsored or co-sponsored by one or more of King's Heath Partners or clinical als where the sponser responsibities are managed by the KHP-CTO, RESPONSIBILITIES ‘The Chief Investigator has overall responsibly forthe conduct ofthe study. In a mui centre study, the Chas coordinating responsibility for reporing serious adverse evens to the KHP-CTO and approving REC. The KHP-CTO wil report to the Medicines anv Healtncere products Regulatory Agency (MHRA) according to the timelines defined in Statutory Intrument 2004/1031 a8 amended from te to time, {Data Monitoring Committge (OMC) may be convened In order to review safety data regularly twoughout the trial ot to commencement of the tral snd when necessary, recommend 2asep2018 FINALY Page 50101 the Chie! Investigator and Sponsor whether to continue, modiy or terminal the tra. This review procedure ul be defined in the protocol ‘The Principal investigator has responsibilty for the research at exch tril site (mlt-centre tra), There should be one Pl foreach research sta. Inthe case of asingle-site Study, the Cl ‘and the PI wil normally be the same person, ‘The Pl is responsible fr informing the KHP-CTO, Cl, o the organising research team, ofa serious adverse events that occur at ther site following the guidelines below. ‘The Sponsor is responsible for ensuring that all elevant information about a SUSAR which occurs during the course of @ clinical til in the United Kingdom and is fatal or Ife- threatening s reported as soon as possible tothe MHRA, the competent authoties of any EEA Stata, other than the United Kingdom, in which the al is being conducted, and the felevant Ethics Commit. This needs to be done ot later than seven days forthe Sponsor was fst aware of the reaction. Any edeltional relevant information should be ‘reported within eight days of the ill report. ‘The Sponsor shall ensure that @ SUSAR which is not fatal or Iife-threataning i reported a8 '800n a8 possible and in any event, not later than fifteen days ster the Sporsor Is fist ‘aware ofthe reaction. ‘The Sponsor must also ensure that, in relation {8 each clinical tal the United Kingdom for Which they are the Sponsor, the investigators responsibie for tha conduct ofa tral are informed of any SUSAR vinich occurs in eaton fo an investigational mecicinal product (IMP) used in that tral, whether that reaction eecurs during the couree ofthat al or another ral for which the Sponsor is responsible ‘Tho KHP-CTO wil act on behalf of the Sponsor ensuring that the Sponsors reporting responsibilities are met, PROCEDURE ‘The Pl wil report all SAES) SARs, SUSARs and IMEs (equivalent to ICH Topic £28 “Other “Medically important Condition’), including pregnancies, immediatly (but no later than 24 rs) the tial staff become aware of the event, to the Cl and Sponsor. All serous events wil Be reported using tha SAE Report Yorm (eas related documants) unless tho, prelscol states ‘therwise, The Cl and PI wil supply any supplementary Information as requetted by the MHRA, REC or KHP-CTO (see related documents) Event and reaction terms should be Coded using the medDRA Lowest Level Term (LLT) most cosoly corresponcing to the Feactiovevent. Claiication and confirmation should be sought from the Chief Investigator (ia responsibie CRA) where a tem is ambiguous or uncles’ and good cinical jedgment to Complete this tem with the best MedDRA approximation ‘The Cl wil ssess the seriousness of each event and the causality between the IMP andlor Concomitant therapy and the adverse event Events may algo be reviewed by the OMC, Treatment codes must be un-blinded for specific subjects, prior to submitting SUSAR ‘reports to the MHRA and REC. “Once treatment has been unlinded the patert wil be ‘withdrawn from the tal (fellow up safety data may be inckided in the overall tial safety 2889/2018 FINAL 84 Page ot 10analysis). Where there is a diference of opinion between Cl and Pl regarding’ SAE/SUSAR. the PI decision will not be downgraded by th Ci ‘The Cl or Pl wil report all SAEs, SARs SUSARs and IMEs to the KHP.CTO as soon {a8 sihe is aware of and has assessed the event. It is the responsibility ofthe Cl to report all SUSARs to the REC. Investigator Reporting to the KHP-CTO All SAEs, SARs & SUSARS, including any folow up information, must be reported using the ‘SAE Report form which is located onthe KP-CTO websiie This form wil be completed and faxed tothe KHP-CTO using the number quoted on the SAE Report Form or e-mailed tothe KHP-CTO using the address quoted onthe form ‘The KHP.CTO will acknowledge receipt ofthe SAE Report using the KHP-CTO SAE Receipt Form (see related documents) I the reporter has not received recept within 24rs of sending the repert (during offce hours), the SAE Raport Farm should be re-sont tothe KHP.CTO by ‘email or fa “The documentation recsived from site wil beteviewed by a member ofthe KHP-CTO Quality Team for completeness and the SAE Checklst (see related documents) willbe completed (end retained by the KHP-CTO), [Additional information, at becomes avilable, wil leo be reported onthe SAE report form land returned to the KHP-CTO by ema or fax as above, ‘The SAE Report Form will be filed in the Trial Master File, the patent's hospital notes, the case record form, the Investigator Ste Fe (f applicable) and the Sponsor fe. [A record of the SAE will be mad@’in the KHP-CTO Pharmacoviglance database by the person accepting and recepting the inal SAE report KHP-CTO Reporting to the MHRA - eSUSAR Reporting [A fatal or Mesthreatening: SUSAR i raported as soon as possila to the NHRA. the Competent authorities of any EEA State, other than the United Kingdom, in which the tial is being conducted, andthe relevant Ethics Commitee not later than seven days after the Sponsor was fst aware of the reacion. Any addtional relevant information should be reported within elght days of the intial report. 'A SUSAR wich isnot fatal or life-threatening is reported as soon a8 possible and, in any ‘event not later than fifteen days ster the Sponsors first aware ofthe reaction, [All SUSARS Wil be reported to the MHRA within the above timelines, using the eSUSAR form ‘which isfound onthe MHRA electronic reprting site for SUSARS hips esusar mhva gov ull ‘The eSUSAR Portal User Guidance Document is a related document to this Policy which details procedures for entering SUSAR information. The following should be noted with ‘respect fo entering seriousness eter and reaction details: 2evSep 2018 FINAL v8 Page 70110+ Seriousness criteria should alvays be entered, Where a SUSAR hae been classed as {an IME on the KHP-CTO SAE Repor, the eSUSAR £28 erteria "Other Medically Important Condition” should be selectec Proananey Safety Reporting ‘Any pregnancy that occurs during tial IMP administration, whist not an adverse event, ‘equires monitoring and folow up to term, Pregnancies and auteome wil be incluced in signal detection and annval safety reports, ‘The Cl or PI will eport any pregnancy occuring on a ciel tal via the SAE resort form to the KHP-CTO in the manner described above. Each pregnancy wil be followed up until outcome of the pregnancy is known, The Cl or PI wil ise with the relevant Obstetrician thoughout the pregnancy ‘A database record ofall pregnancies will be held by the KHP-CTO, tis wil include flow up ta term an were appropiate, long-term folow up ofthe baby may be required Important Medical Events important Medical Events that may not be mediately lte-theatening or resutin death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes lsied in the definition above should also be considered serious and reported using the SAE repor orm. Urgent Safety Mes ‘The Regulations allow the sponsor and investigator to take appropriate urgent safety ‘measures to protect clinical trial subjecis trom ary immediate hazard to ther health and Safely; these measures should be takan immediately but the Sponsor must not the MHRA, ‘and the REC in writing, ofthe measures taken and the reason for the measures within 3 days ‘by submiting a substantial amendment (annex 2). The CI must inform the KHP-CTO ae soon 48 possible after the implementation of the urgent safety measures. The Cl or Sponsor ‘must phone the MHRA's Clinical Trial Unit on 020 3080 6456 to discuss the issue wth & Safety Scientia ideally within 24 hours ‘The MHRA wil inform you how to submit the substantial amendment to them within 3 days When you speak to them, but it will usually be by ema. ‘The decision to undertake appropriate safely measures may be taken by +The Gandior PI *+ The KHP-CTO - on behalf ofthe Sponsor and in consultation with the Cl or DMC. ‘Ongoing safety evaluation of any MP(s ‘The KHP-CTO will ensure thatthe Cl promptly notifies all other Investigators, REC(e) and MHRA of any findings that may affect the haath of subjects. The KHP-CTO wil ensure that 2ev9ep2018 FINAL vad Paget 10ail Investigators using the same IMP in diferent trials are notified if new Safely information comes to ight ‘A concise safety analysis and rsk-beneit evaluation deserbing all new inings related to the Ssfely of the IMP treatments wth respac other impact forthe subjects wl be corsiered by the Pl Cl and OMC (if applicable). Development Safety Update Reports ‘The KHP-CTO wil ensure that a DSUR is sent to the MHRA and REC annual ‘The DSUR willbe submitted tothe MHRA (and any othet maftber state Competent Authority wine the trial is being conducted) and approving REC no later than 60 calendar days ater the DSUR data lock point ‘A copy ofthe report wil be fled inthe TMF and Sponsor File. ‘Any SAE that falls within the criteria defined in the Sponsors Clinical Incident or Risk ‘Management Poly wil be addonally reported fo the Cinical Governance/Risk Management Team ae detalid in the local pokey. [RELATED DOCUMENTS Serious Adverse Event Report Fort ‘Serious Adverse Event Receipt Form Serious Adverse Event Checklist ‘@SUSAR User Guidance Document 2e80p2018 FINALS: Page ot 10APPROVAL and St Oo Ce 26oqloore “ae Puen ie Director king's Heatth Partners Clinical Trials Office KS eamine Serpe ‘280920 FNAL Wet Page t0ot10