Dear Senior Coroner Harris, Thank you foryour Reportdated 10th 2019 to which timeline of 2nd July 2019. The incident; we respond in accordance with the required attention by University College hehich is the subject Of your Report; Was broughtewo ced standard London, the Sponsor of Cardamon Study ('Study' ), reporting obligations to Amgen Limited as part of its holder (MAH) of study Kyprolis" ('Amgen"), the marketing authorization '(carfilzomib), on 12th February 2018 We refer to Section 5.2 ofyour Report which seeks our response in relation to following concern: expert pharmaceutical physiciun gave recommendation monitoring was made more definitive in the that the need for cardiac possibly others) which was prescribed in the prescribing information for Carfilzomib (and Cardamon Trial We take all adverse event ('AE) reporting internally at Amgen and at European seriously at Amgen; Governance processes, both Assessment Committee ('PRAC') level, iedicines: Agency (EMA') and Pharmacovigilance Rsk regular basis to establish the inandate that AE data, such as in this case, Is evaluated on benefit risk proflle of authorised medicinal whether adjustments are needed in the Summary products and determine Information Leaflet ("PIL') The of Product Characteristics ('SmPc) and Patient (EMAPRAC) and the MAH; process in EU is a collaboration between the agency therefore be imilateral update to the SmPc based on one case aleee,thoulc possible as examination of extensive medical not required prior to any SmPC change evidence by all stakeholders would be Implemented, The current SmPC for Kyprolis lists cardiac failure and and myocardial infarction as an uncommon myocardial ischaemia as common side effects and precautions for use' for tide effect in section 4.8 and contains 'special warnigs
4.4: patients both with and without pre-existing cardiac conditiona in Section or "worsening cardiac failure (e.g: congestive cardiac failure; _ ejection fraction) myocardial ischaemia and infarction pulmonary oedemd, decreased Kyprolis. Death due to cardiac arrest has have occurred following administration of outcomes have been occurred within 4 of Kyprolis administration and fatal reported with cardiac failure and myocardial infarction". Registered Office: 240 Cambrirlge Science Park Mikton Road, Camhridge, CBA OWD Registered No. 2354269 May the safetv the drug; the "The drug very labeling the being "New day"

SmPC warns that an increased risk Of cardliac failure exists in patients with a medlical history of cardiac disorder, the elderly and patients of Asian ethnicity, further, that patients with signs or svmptoms of NYHA Class IIl or IV cardiac failure; recenthistorv of myocardial infarction, uncontrolled angina or arrhythmias "should be treated with caution and remain under close follow-up. The Patient Information Leaflet ('PIL') for Kyprolis (A2) , which contains in lay terms the same warnings, precautions and side effect information, states at section 2 "Your doctor will examine you and review your jull medical history: You will be monitored closely during treakment" and continues to specifically warn patients to talk to thelr doctor about any existing heart problers in case additional tests are required prior to Kyprolis: There are no warnings or recommendations in the SmPC or PIL for patients without a history of cardiac clisorder As Amgen was not the Sponsor of StudV, we do not have sufficient inforration to determine whether the patient had cardiac at time of enrollment, or not; We therefore consider that cardiac monitoring guidance is already definitively outlined in the prescribing information for Kyprolis: As the guidance provided in the current SmPC has been approved by PRAC and EMA, We believe that no further revisions to the SmPCare required: We will however, continue to conduct ongoing pharmacovigilance of Kyprolis and to evaluate our SmPc guidance on cardiac monitoring, in accordance with all pharmacovigilance requirements. We trust that this information will serve to resolve your concern and this matter to a close, but please do not hesitate to contact us If we can be of any further assistance.

Dear Sir

Response to Regulation 28 Report to Prevent Future Deaths: Edward Hearn (Deceased)

We write further to the above Report dated 8 May 2019 and detail the Trust‟s formal response below.

As a preliminary point, we note that in relation to the one matter of concern you raised in your Report and and which was directed to the Trust, you state that “…it did not contribute to [the] death” of the Deceased, on page 9 of your Judgment dated 8th May 2019.

Matter 1

The finding of a high globulin by a laboratory from a blood test in A&E was not followed up by either the laboratory or A&E department. It was not in College guidelines of tests, which required urgent notification. It was indicative of a fatal disease, which was not diagnosed for approximately another 4 months. I accept the professional opinion of the haematologist that this was a system failure, which is not acknowledged by the Trust. The laboratory suggested an additional action to have an automated comment but that would still not deal with the problem of reports returning to physicians in secondary care. Evidence was heard that there is inconsistency in laboratory repeating and alerting of clinicians even between hospitals in the jurisdiction, and insufficient evidence of a safe system within the Trust.

Trust response:

The Trust recognises that a raised globulin (a constituent of total protein, which itself was elevated) as a component of liver function tests (LFTs) was not acted upon following an inpatient medical admission with pericarditis in August 2017, and that multiple myeloma was diagnosed in December 2017, when the Deceased presented at the Trust.

It is however the case that there are multiple common causes for elevated protein, including dehydration, chronic inflammatory states, alcoholic liver disease,

autoimmune disease, amyloidosis (build-up of abnormal proteins in organs), infections, hepatitis B or C, HIV or AIDS, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.

The reason for the different laboratory practices of two of the Trust hospitals, the Princess Royal University Hospital (PRUH) and King‟s College Hospital (KCH), is that the critical difference between the PRUH and KCH, is that as the Institute of Liver Studies is located at KCH, the patient population treated by KCH has a high prevalence of HIV and hepatitis, and therefore a large portion of KCH patients will have a raised globulin level. Accordingly, carrying out extensive investigations on every sample with high total protein at KCH has poor clinical utility.

The poor clinical utility of such an approach is reflected by the fact that two similar size neighbouring NHS Trusts, Guy‟s and St Thomas‟ NHS Foundation Trust, and University College London Hospitals NHS Trust, do not perform routine globulin testing as part of the liver profile.

The Trust follows the Royal College of Pathologists‟ recommendations by telephoning out critical results to the requesting clinician or teams, 24 hours a day. Neither the recommendations in place at the time, „Out-of-hours reporting of laboratory results requiring urgent clinical action to primary care: Advice to pathologists and those that work in laboratory medicine, November 2010‟, nor the recommendations superseding that document, „The communication of critical and unexpected pathology results, October 2017’, identify elevated total protein as a result that needs to be communicated to the requester as a critical limit.

The Emergency Department (ED) treating doctor did not note the raised total protein and globulin found on the sample sent on 12 August 2017. This case is being used to highlight to ED medical staff the importance of noting abnormal blood test results and ensuring appropriate follow-up (outpatient or GP). Work is also ongoing to highlight to clinical teams the importance of reviewing test results on inpatients daily. The Trust uses a system called „Safety Net‟ to circulate key learning themes for clinical teams to be aware of. A Safety Net is being prepared in relation to raised protein/globulin and the association with multiple myeloma. The „Screening Diagnostic Improvement Group‟ looks at systems to ensure that test results are reviewed promptly to reduce clinical risk. This Prevention of Future Deaths Report will be reviewed in that meeting to ensure that relevant actions are put in place to prevent a recurrence. The timetable for the above actions is from the time of writing (for the work with ED medical staff and highlighting to the clinical teams), whilst the Safety Net will be prepared by the end of August 2019. The Screening Diagnostic Improvement Group will meet on 19 August 2019, and this group‟s work remains ongoing.

We agreed that KCH and the PRUH standard lab comments to GP‟s for outpatient Biochemistry will be aligned. We plan to review the Biochemistry profiles that we provide to GP‟s and to implement these changes by the end of July 2019, (as the KCH and PRUH laboratories are currently part of a platform alignment project which requires significant IT support), with a view to standardising reporting across the Sustainability and Transformation Partnership. We plan to audit the number of referrals to the Plasma Cell Disorders service one year after instituting this change.

We trust you are satisfied with the response to the above matter of concern you have raised.

Dear Dr. Harris, [Cove ReFuture Deaths Report for Edward Hearn Date Of Death (05. (Case Ref: 00395-2018) .02.2018) Thank you for copying to the MHRA your report dated 10 2019, the Coroners under paragraph 7, schedule 5, of and Justice Act 2009 and regulations 28 and 29 of the Coroners Regulations 2013, concerning the death of Mr Edward Hearn; Who died (Investigations) College on Sth February 2018 in King's Hospital, (0395-18). This case report been added to the MHRA's Yellow 'adverse drug reactions with the reference Card database of ADR 24406875. Further to the information provided on this tragic and in accordance with your request; we have considered whether the statutory information currentiy provided by the marketing for prescribers (and patients) on the safe use of authorisation holder carfilzomib, is adequate , and whether any other regulatory measures could be taken to minimise the risk of cardiac arrest in subjects exposed to this The statutory productinformation for cyclophosphamide and dexamethasone; with carfilzomib to treat Mr Hearn, used in combination was also considered, To this end, we have sought the advice of the Pharmacovigilance Expert_ Group (PEAG) , an independent advisory group to the Commission on Human Medicines on matters of safety. Information on the use of medicines is provided to healthcare Product professionals through the Summary of Characteristics (SmPC) and to patients through Patient Information Leaflet of the SmPCs and PILs may be found on the MHRA's (PIL): Full details website (http-Ilwwmhra gov uklspc-pil) and the electronic medicines compendium (httpsJlwmedicines orq uklemcl) {axk dad I {k May has case, drug; Advisory drug the dscb1

Carrilzomib (Kyprolis) In corbination with either lenalidornidle alone is indicated for tne ancl clexarethasone or dexarethasone treatrent of adult patienis with multiple myelora one prior therapy: who have received at least Cyclophosphamide, drug roported a8 comedication in the case of Mr: Hearn; authorised for treatment of a number Of is combiration of cancers, including multiple myeloma_ The specitic 'carilzornib, cyclophosphamide &nd dexamethasone is however not - outside of clinical trial use_ currently authorised Section 4.4 (Special warnings and precautions for 0f use) 'te SmPC for carfilzomib states that new or worsening cardiac failure including fatal cases of myocardial within a day following ischaemia and infarction has occurred administration ofthe drug: The corresponding section for that acute cardiac toxicity including severe QT 'cyclophosphamide states as 20 mglkg of prolorigation been reported with slngle doses as Iow cyclophosphamice (please see Annex 4) The patient inforration leaflets products include information which reflects Of the two the SmPC_ Therefore, on review of the available information, and in relation to actions we are satisfied within the remit of the MHRA, that the statutory SmPC and PIL for the medicines concerned in the case of Mr. Hearn currentiy provide relevant information to highlight the risk of serious cardiac disorders. However; as we have reports of a total of 10 cases (including the case of Mr Hearn) of cardiac arrest, myocardial infarction or cardiac failure with carfilzomib, the PEAG has prescribing the and recommended that doctors cardiologists should be reminded of the requirements to monitor cardiac disorders before and during treatment patients for with carfilzomib Thls information will be provided via an article in the MHRA's electronic bulletin for healthcare 3 months. We professionals, Study Update, in the next 2- will you informed Yours Chief Executive Medicines and Healthcare products Regulatory the has drug Drug keep sincoro Agency

Annex 1 Section 4.4 (Speciai warnings and precautions for use) Cardiac disorders New Or worsening cardiac failure (e.g: congestive cardiac failure, pulmonary oedera, decreased ejection fraction) myocardialischaemia and infarction have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a of Kyprolis administration and fatal outcores have been reported with cardiac failure and myocarclial infarction. While adequate hydration is requirec prior to dosing in cycle 1, all patients should be monitored for eviderce of volume overload, especially patients at risk for cardiac failure. The total volume of fluids may be adjusted a8 clinically indicated in patients with baseline cardiac fallure or Who are at risk for cardiac failure (see section 4.2) Stop Kyprolis for grade 3 or 4 cardiac events until recovery and consider whether to restart Kyprolis at 1 dose level recuction based on a benefitlrisk assessment (see section 4.2). The risk of cardiac failure is increased in elderly patients ( 75 years). The risk of cardiac failure is also increased in Asian patients. Patients with New York Heart Association (NYHA) Class IIl and IV heart failure [moderate to severe]; recent myocardial infarction; and conduction abnormalities uncontrolled by medicinal products were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications, Patients with signs or symptoms of NYHA Class IIl or IV cardiac failure, recent history of myocardial infarction (in the last 4 months), and in patients with uncontrolled angina or arrhythmias, should have a comprehensive medical assessment; prior to starting treatment with Kyprolis This assessment should optimise the patients status, with particular attention to blood pressure control and fluid management Subsequently patients should be treated with caution and remain under close follow-up. Electrocardiographic changes There have been cases of QT interval prolongation reported in clinical studies. An effect of Kyprolis on QT interval cannot be excluded (see section 5.1). Section 4.8 (Undesirable effects) Very common Common Uncommon Rare 1/10) 1/100 to < 1/10) 1/1,000 to 1/10,000 to N1OO)) NLOOO) Cardiac Cardiac failure Cardiac arrest disorders Myocardial Myocardial infarction ischaemia Atrial fibrillation Pericardilis_ day

TTachycardia Pericardial eifusion Ejection fraction decreased Palpitations Cyclophosphamide SmPC Section 4,4 (Special warnings and precautions for lse) Cardiotoxicity, Use In Patlents with Cardiac Disease Myocarditis and myopericarditis, which may ba cardiac tamponade, accorpanied by significant pericardial effusion and have been reported with cyclophosphamide sometimes fatal and have led to severe, congestive heart failure. Histopathologic examination myocardlitis. Hlaemopericardium has been primarily shown hemorrhagic reported secondary to hemorrhagic myocarditis myocardial necrosis. Acute cardiac toxicity has been and cyclophosphamide. reported with single doses as low as 20 mg/kg of Following exposure to treatment regimens that included arrhythmias (including atrial fibrillation and cyclophosphamide, supraventricular as well a8 ventricular arrhythmias QT prolongation associated with ventricular (including severe without other tachyarrhythmia) have been reported In patients with and signs of cardiotoxicity. The risk of cyclophosphamide cardiotoxicity as a result of treatment with example, be increased following cyclophosphamide may, for high doses of cyclophosphamide, in patients with advanced in patients with previous radiation treatment of age, and the cardiac region andlor previous or treatment with other cardiotoxic agents. See section 4.5. concomitant Particular caution is required in patients with risk factors for existing cardiac disease. cardiotoxicity and in patients wth a pre- Section 4.8 (undesirable effects) Common Uncommon Rare common 1/100 (2 1/1,000 to 1/10,000 to Unknown (z W10) to < MO)
1100) rare Cardiac NL,OOO) disorders Cardiomyopathy Ventricular Ventricular Ventricular Myocarditis arrhythmia fibrillation tachycardia Heart failure Supraventricular Angina Cardiogenic arrhylhmia shock Myocardial infarction Pericardial effusion Perlcarditis Bradycardia Atrial fibrillation Palpitations Electrocardiagram QTprolonged therapy has flutter) : Very Very

Medicines Healthcare proclucts Regulatory Agency MHRA Andrew Harris Mhra Coroner for Inner South District; Southwark Coroners Court Tennis Street; Southwark 10 South Colonnade SE1 YD Canary Wharf London E14 4PU Date 23/05/2019 United Kingdom gov.uklmhra ZAu 610z NIT 5 0 Dear Harris, @33334 Local Identification Number: Patient Initials: EH Patient Age: Patient Sex: Male Yellow Card Reference Number: ADR 24406875 Thank you for reporting a suspected Adverse Drug Reaction, a copy Is enclosed for your records, Ifzadditional information becomes available about your patient you can email this to Yelowcaromhracovuk write t0 us at FREEPOST YELLOW CARD' or cali our Yellow Card information Service on 0808 100 3352 (1Oam to Zpm Monday-Friday). To us link all correspondencea please quote the above Yellow Card reference number_ Please femove patient personal identifiers such as name and date of birth from all information supplied; Where possible; Whicfocaratorogheld Inistrict confidence and handled in line with our Yellow Card Privacy Pollcy, which can be found at httos Lyvellowcard mhra GOV Uklprivacv-policvl If you wish t0 of the information we hold on your Case or a copy oi your reporoaSVf appearsish Our Gatatssecopy please write t0 us at the address above or email yellow card@mhra database, reference number and details of gvuk your case your request: You can find out more about the suspected Adverse Reactions we have received WWWmhra gQv uklyellowcard: at Additionally, you can Uptto-date on the latest advice for the safe use of medicines by reading our monthly bulletin Safety Update,which is available on our website at WWW goVukldrug safety-update You can receive a notification Of each new bulletin by sending your email address to registratlon@mhradrugsafetyorguk: GhecYellow Card Scheme is very important tor early detection of previously unrecognised adverse Offectseand allows u8 to take appropriate action t0 improve the safe use of medicines SYouFGvllow Card report is a valuable contribution to monitoring the safety of medicines in the UK; Thank you again_ Submit Yellow Cards and view furlher information online at wwmhre gov uklyellowcard YellowCard Download the Yellow Card App for free now. Available on iOS and Android help citing Drug stay Drug

Yellow Card Helping t0 make medicines saler MHRA Report Overview GB-! ~MHRA-ESUSAR-203630347001-00101763 Suspect Reaction Suspect Reactions Added Ouicome of the Reaclion Start Dale End Dale Cardiac arrest falal 03/02/2018 05/02/2018 Bronchopneumonie; organism unspeclied fatal 2018 Sepsis faltal 2018 Do you consider the reaction to be serious? Yos Reaction severity Patlent dled due to reaction; Date of death 05/02/2018 Suspect Medicine Brand Batch Action Start Date End Dale Indication taken for Methcd Source reaction Carillzomlb Carfillzomlb 22/01/2018 02/0212018 Muitlple myeloma wilhdrawn CYCLOPHOSPHAMIDE CYCLOPHOSPHAMIDE 22/01/2018 01/02/2018 Mulflple myeloma withdrawn DEXAMETHASONE DEXAMETHASONE 22101/2018 01/0212018 Multiple myeloma wlthdrawn Additional informatlon Trial Name: Cardamon Carfizomib/Cyclophosphamide/Dexamethasone with maintenance carfilzomib in untrcated transplant-ellgible pallents with symptomatic MM (o evaluate the henofit of upfront ASCT. Pallent number: CAR-181 receivlng trealment for Symptomatic Mulllple Mveloma on the aforemenlioned clinical trial; CAR-181 was in the inductlon phase of the Irial Tha IMPs In Induction are carilzomib, cyclophosphamide and dexamethasone _ InIhe induotion phase of (he frial, the paliont receives cyclical Ireatment, with carfilzomib belng given on 1,2, 8, 9, 15 and 16 over 28 dey cycle. Patients receive oyclophosphamide and dexamethasone on 1, 8 and 15 of each "cyclo. The patient slarted cycle 22101/2018 receiving all IMPs a8 per prolocoi. The palient had completed delayed 9 of cycle on 02/02/2018 when he experlenced (he reaction. The patient was an In-patlent being managed conservallvely for Trac{ure of the hip sustained on 29/01/2018 fall, Palicnt recaived cycle day 8 on 01/02/2018 and 9 on 02/02/2018_ The paticnt was treated jof 2 fever on 02/02/2018 On 03/02/2018 Ihe pallent experienced 2 asystolic cardiac arrests: The patient was admllted to ITU where upon 9t spontaneous circulation on 04/02/2018 they hed fxed dlated pupils EEG performed on 05/0212018 showed no consistent €orfom acllvity inkeeplng with Gevere hypoxlc encephalopathy. Death confirmed 17:00 05/02/2018. The Patient had no previous cardiac history and recent" ECHO ad cardlac MRI were both normal. The report was recelved by the Sponsor on 05/02/2018. Cardlac arrest was assessed as related by lhe sle Evestigator Io carfizomib and Was assessed by Ihe Sponsor as unexpected for carlilzomib hence meeling te delinition of a day SUSAR (0 cariilzomlb The trial Clinlcal Reviewer concurs with tne site Investigator that cardiac arrest Is causally related to carfilzomib. The clinlcal reviewer aiso assessed cardlzc arrest a8 related to cyclophosphamlde Therefore as cardiac arrest was asscssed a8 unexpecled for cyclophosphamlde by the Sponsor; the event also meets {he definilion of a day SUSAR t0 cyclophosphamido The event of cardlac arrest was assessed as fatal 05/02/2018; The results of a post-mortem are currently outstanding: UPDATE 19/11/2018 The treating site now have access to Ihe coroners report which states cause of dealh as {a) bacterial bronchopneumonia; 1b) teft ventricular hypertrophy Ic) myeloma As a result of Ihe coroners repart"s flndings 'infection bacterlal bronchopnoumonla' and 'sepsis' reactions have been added (0 the SUSAR report Bronchopneumonla (fatal) was assessed as relaled by Ihe site investigator to carilzomib, oyclophosphamide and dexamethasone Brorchopncumonia (falal) was assessed by the Sponsor as unexpected for carfilzomlb and dexamelhasone and expected for cyclophosphamide hence meeting the definlllon of a SUSAR to carfilzomib and dexamelhasone. Sepsls (fatal) was assessed as related by the site investigator t0 carfilzomib, cyclophosphamide and dexamethasone and was assessed the Sponsor a8 unexpected for carfilzomib, cyclophosphamide dexameihasone hence meeling the definaton ofa SUSAR tGarflzortih; cyclophosphamide and dexamelhasone The (rlal Clinlcal Revlewer concurs wlh the site Invesligator (hat bronchopneumonia ((atal) and sepsls (fatal) are causally related t0 carfilzomib, cyclophosphamide and dexamethasone Drug Dosage Drug Drug Orug day " day " day - due day = and and

Medicines Healthcare products Regulatory Agency MHRA