Edward Hearn

Amgen Limited

240 Cambridge Science Park
Milton Road

Cambridge

CB4 OWD

Tel: 041223 420305

Fax: 01223 228115

Senior Coroner Andrew Harris

inner South District Greater London,
Southwark Coroner’s Court,

1 Tennis Street,

Southwark

SE1 1Yp

4 july 2019

Re: Prevent Future Deaths Report for EH ‘Report’

Date of Death (05.02.2018) (Case Ref. 00395-2018)

Dear Senior Coroner Harris,

Thank you for your Report dated 10¢% May 2019 to which we respond in accordance with the required
timeline of 2nd July 2019, The incident, which is the subject of your Report, was brought to our
attention by University College London, the Sponsor of the Cardamon Study (‘Study’), as part of its
standard safety reporting obligations to Amgen Limited (‘Amgen’), the marketing authorization
holder (MAH) of the study drug, Kyprolis® (carfilzomib), on 12" February 2018.

We take all adverse event (‘AE’) reporting very seriously at Amgen, Governance processes, both
internally at Amgen and at European Medicines Agency (‘EMA’) and Pharmacovigilance Risk
Assessment Committee (‘PRAC’) level, mandate that AE data, such as in this case, is evaluated on a
regular basis to establish the benefit risk profile of authorised medicinal Products and determine

t Characteristics (‘SmPC’} and Patient

(EMA/PRAC) and the MAR. A unilateral! update to the SmPc

therefore be possible as examination of extensive medical evidence by all stakeholders would be
required prior to any SmPC change being implemented,

The current SmPC for Kyprolis lists cardiac failure and myocardial ischaemia as common side effects
and myocardial infarction as an uncommon side effect in section 4.8 and contains ‘special warnings

and precautions for use’ for patients both with and without pre-existing cardiac conditions in Section
44:

“New or worsening cardiac failure (e.g. congestive cardiac failure, pulmonary oedema, decreased
ejection fraction), myocardial ischaemia and infarction have occurred following administration of
Kyprolis, Death due to cardiac arrest has occurred within q day of Kyprolis administration and fatal
outcomes have been reported with cardiac failure and m yocardial infarction”.

Registered Office: 240 Cambritige Science Park, Milton Road, Cambridge, CB4 owD
Registered No, 2354269

The SrmPC warns that an increased risk of cardiac failure exists in patients with a medical history of
cardiac disorder, the elderly and patients of Asian ethnicity, further, that patients with signs or
symptoms of NYHA Class Ill or lV cardiac failure, recent history of myocardial infarction, uncontrolled
angina or arrhythmias “should be treated with caution and remain under close follow-up.” The
Patient Information Leaflet (‘PIL’) for Kyprotis (A2), which contains in lay terms the same warnings,
precautions and side effect information, states at section 2 “Your doctor will examine you ond
review your full medical history. You will be monitored closely during treatment” and continues to
specifically warn patients to talk to their doctor about any existing heart problems in case additional
tests are required prior to taking Kyprolis. There are no warnings or recommendations in the SmPC
or PIL for patients without a history of cardiac disorder.

As Amgen was not the Sponsor of the Study, we do not have sufficient inforrnation to determine
whether the patient had cardiac history 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 SmPC are required. We will
however, continue to conduct ongoing pharmacovigilance of Kyprolis and to evaluate our SmPC
guicance on cardiac monitoring, in accordance with all pharmacovigilance requirements.

We trust that this information will serve to resolve your concern and bring this matter to a close, but
please do not hesitate to contact us if we can be of any further assistance.

Yours sincerely,

Medical Director, UK & Ireland

Page 2

Your ref: 
Our ref: 

1 July 2019 

Mr Andrew Harris 
Senior Coroner 
Southwark Coroner‟s Court 
1 Tennis Street  
Southwark  
SE1 1YD 

Dear Sir 

Legal Services 
King‟s College Hospital 
Denmark Hill 
London SE5 9RS 

Tel: 020 3299 3320 
Fax: 020 3299 3706 

Direct dial:

Email: 

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 
jurisdiction,  and 
insufficient evidence of a safe system within the Trust. 

in  the 

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, 
liver  disease, 
including  dehydration,  chronic 

inflammatory  states,  alcoholic 

 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 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.  

follows 

the  Royal  College  of  Pathologists‟  recommendations  by 
The  Trust 
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 
„Screening 
protein/globulin  and 
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. 

the  association  with  multiple  myeloma.  The 

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.  

Yours faithfully 

Legal Services

Meclicines & Healthcare products

: Regulatory Agency
Dr Harris Medicines & Healtheare products
Southwark Coroner's Court, Regulatory Agency
i Tennis Siresi, 10 South Colonnade
Southwark. Canary Whart
Onden

SETYD E14 4Pu

United Kingdom

+44 (0) 20 3080 6000
17 June 2019 gov.uldmbra

Dear Dr. Harris,

Prevent Future Deaths Report for Edward Hearn Date of Death (05.02.2017 8)
(Case Ref: 00395-2041 8)

Thank you for Copying to the MHRA your report dated 10 May 2019, under paragraph 7, schedule 5, of
the Coroners and Justice Act 2009 and regulations 28 and 29 of the Coroners (Investigations)
Regulations 2013, concerning the death of Mr Edward Hearn, who died on 5th February 2018 in King's
College Hospital, (0395-18). This case report has been added to the MHRA’s Yellow Card database of
‘adverse drug reactions with the reference ADR 24406875.

Further to the information provided on this tragic case, and in accordance with your request, we have
considered whether the Statutory information currenily provided by the marketing authorisation holder
for prescribers (and patients) on the safe use of carfilzomib, is adequate, and whether any other
regulatory measures could be taken to minimise the tisk of cardiac arrest in subjects exposed to this
drug. The statutory product information for cyclophosphamide and dexamethasone, used in combination
with carfilzomib to treat Mr Hear, was also considered. To this end,
Pharmacovigilance Expert Advisory Group (PEAG), an inde:
on Human Medicines on matters of drug safety.

we have sought the advice of the
pendent advisory group to the Commission

Information on the use of medicines is provided to healthcare professionals through the Summary of
Product Characteristics (SmPC) and to patients through the Patient Information Leaflet (PIL). Full details

of the SmPCs and PiLs may be found on the MHRA’s website (htto:/mww.mhra.gov.uk/spc-pil/), and the

electronic medicines compendium (hitos: /www.medicines.org.uk/eme/).

lie

Cariiizomib (Kyprolis) in combination with either lenalidernide and dexameth
alone is indicated for the treatment of aciuit patients with m
one prior therapy. Cyclophosphamide, a drug reported as
authorised for the treatment of @ number of cancers, in

asone or dexamethasone
ultiple myeloma who have received ai least
comedication in the case of Mr. Hearn, is

cluding multiple myeloma. The specific
combination of Carfilzomib, cyclophosphamide and dexamet

outside of clinical trial use.

Section 4.4 (Special warnings and precautions for use) of the SmPC for carfizomib siaies that new or

worsening cardiac failure including fatal cases of myocardial ischaemia anc infarction has occurred

ig Severe QT prolongation has been reported with single doses as low
as 20 ma/kg of cyclophosphamide. (please see Annex 4

). The patient information leaflets of the two
products include information which reflects the SmPC.

Therefore, on review of the available information, and in relation to actions within the rernit of the MHRA, \-
we are satisfied that the statutory SmPC and PIL for the medicines concerned in the case of Mr. Hearn
currently 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 recommended that doctors
prescribing the drug and cardiologists should be reminded of the requirements to monitor patients for
cardiac disorders before and during treatment with carfilzomib. This

article in the MHRA’s electronic bulletin for healthcare professionals, Drug Study Update, in the next 2- :
3 months. We will keep you informed. |

information will be provided via an

Chief Executive
Medicines and Healthcare products Regulatory Agency

Annex 1

Section 4.4 (Special warnings and precautions for use)
Cardiac disorders
New or worsening cardiac failure (2.9. congestive cardiac failure, pulmonary oedema, decreased
ejection fraction), myocardial ischaemia and infarction have occurred following administration of Kyprolis.
Death due to cardiac arrest has occurred within a day of Kyprolis administration and fatal outcomes have
been reported with cardiac failure and myocardial infarction.
While adequate hydration is required prior to dosing in cycle 1, all patients should be monitored for
evidence of volume overload, especially patients at risk for cardiac failure. The total volume of fluids may
be adjusted as clinically indicated in patients with baseline cardiac failure 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 reduction based on a benefit/risk assessment (see section 4.2),
The risk of cardiac failure is increased in elderly patients (2 75 years). The tisk of cardiac failure is also
increased in Asian patients.
Patients with New York Heart Association (NYHA) Class III and IV heart failure [moderate to severe],
recent myocardial infarction, and conduction abnormalities uncontrolled by medicinal products were not
cligibie for the clinical trials. These patients may be at greater risk for cardiac complications, Patients
with signs or symptoms of NYHA Class III 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
patient's 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 (2| Uncommon @] Rare e
(2 1/10) 1/100 to < 1/10) 11,000 to < 1/10,000 to <
11100) _ [ 1,000) _
Cardiac Cardiac failure Cardiac arrest
disorders
Myocardial Myocardial
infarction ischaemia

Atrial fibrillation Pericarditis

Tachycardia Pericardial
effusion

Ejection fraction .

decreased

Palpitations

Cyclophosphamide SmPC

Section 4.4 (Special warnings and precautions for use)
Cardiotoxicity, Use in Patients with Cardiac Disease

without other signs of cardiotoxicity.
The tisk of cyclophosphamide cardiotoxicity as a result of tre
example, be increased following high doses of cyclophosphamide, i

treatment with other cardiotoxic agents. See section 4.5,

Particular caution is required in patients with risk factors for

cardiotoxicity and in patients with a pre-
existing cardiac disease,

Section 4.8 (undesirable effects)

Very Common | Uncommon Rare @ Very Unknown
common (2 400 (2 1/1,000 to 1/10,000 to < rare
110) | to<40) |< 1/100) 41,000)
Cardiac Cardiomyopathy | Ventricular Ventricular | Ventricular
A arrhythmia fibrillation tachycardia
disorders Myocarditis
Supraventricular Angina Cardiagenic
Heart failure arrhythmia shock
Myocardial
infarction Pericardial
effusion
Pericarditis
Bradycardia
Atrial
fibrillation Palpitations
Electrocardiogram
Jt QT prolonged

pee a
ay

Medicines & Healthcare products

Reguiatory Agency

Andrew Harris MHRA

Coroner for Inner South District, Southwark Coroner's Court 10 South Colonnade
1 Tennis Street, Southwark Canary Wharf

SE1 1¥D ; London

Of E14 4PU
Date 23/05/2019 ; <p | ‘ap United Kingdom
— » fe - gov.uk/mhra
Que.
Liha

O02 NAT & 9
a Dear Harris, CAI | 0) SI ay

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,

If additional information becomes available about your patient you can email this to
yellowcard@mhra.gov.uk, write to us at ‘FREEPOST YELLOW CARD’ or call our Yellow Card
Information Service on 0808 100 3352 (10am to 2pm Monday-Friday). To help us link all
correspondence, please quote the above Yellow Card reference number. Please remove patient
personal identifiers such as name and date of birth from all information supplied, where possible.

All information is held in strict confidence and handled in line with our Yellow Card Privacy Policy,
which can be found at htips://velloweard, mhra,gov.uk/privacy-polley/. if you wish to request a copy
of the information we hold on your case or a copy of your report as it appears in our database,

please write to us at the address above or email yellow.card@mhra.gov.uk citing your case
reference number and details of your request.

You can find out more about the Suspected Adverse Drug Reactions we have received at

www.mhra.gov.uk/yellowcard.

Additionally, you can stay up-to-date on the latest advice for the safe use of medicines by reading
"our monthly bulletin Drug Safety Update, which is available on our website at www.gov.uk/drug-
Safety-update., You can receive a notification of each new bulietin by sending your email address to

registration@mhradrugsafety.org.uk.

The Yellow Card Scheme is very important for early detection of previously unrecognised adverse
effects and allows us to take appropriate action to improve the safe use of medicines. Your Yellow
Card report is a valuable contribution to monitoring the safety of medicines in the UK.

“Thank you again.

Submit Yellow Cards and view further information

online at www. mhra.gov.uk/yelloweard

Download the Yellow Card App for free now.
Available on iOS and Android

Helping: hake medicines sater

Report Overview - GB-MHRA-ESUSAR-203630347001-00101763

Suspect Reaction

p R O Add Oo ome oO eRe o D dD
Cardiac arrest fatal 03/02/2018 05/02/2018
Bronchopneumonia, organism unspecified fatal 2018 -

Sepsis fatal 2018 -

Do you consider the reaction to be serious?
Yas

Reaction severity
Patient dled due to reaction,

Date of death
05/02/2018

Suspect Drug

Action

+ Medicine~ i Brand. *---- - No. > Start-Date --End Bale: ~Dosage.—Indication _ ‘taken for..: Method. Source™

reaction

Carfizomib Carfilzomib - 22/01/2018 02/02/2018

- Multiple Drug
myeloma — withdrawn

CYCLOPHOSPHAMIDE CYCLOPHOSPHAMIDE - 22/01/2018 01/02/2018 - Multiple Drug
myetoma withdrawn

DEXAMETHASONE DEXAMETHASONE - 2201/2018 01/02/2018 - Multiple Drug

myeloma withdrawn

Additional information

Trial Name: Cardamon - Carfiizomib/Cyclophosphamide/Dexamethasone with maintenance carfiizomib in untreated transplant-eligibie
patients with symptomatic MM to evaluate the benefit of upfront ASCT, Patient number: CAR-181 receiving treatment for Symptomatic
Multiple Myeloma on the aforementioned clinical tal. CAR-181 was in the industlon phase of the tral. The IMPs in Induction ara carfilzomib,
cyclophosphamide and dexamethasone, In the induction phase of the trial, the patient receives cyclical treatment, with carfilzomib belng
given on day 1, 2, 8, 9, 45 and 46 over a 28 day cycle. Patients receive cyclophosphamide and dexamethasone on day 1, 8 and 15 of each
‘cycle, The patient started cycle 1 on 22/01/2018 receiving all IMPs as per protocol. The patient had completed a delayed day 9 of cycle 1
on 02/02/2018 when he experienced the reaction. The patient was an in-patient being managed conservatively for a fracture of the hip
sustained on 29/01/2018 due to a fall. Patient received cycle 1 day 8 on 01/02/2018 and day 9 on 02/02/2018. The patient was treated for a
fever on 02/02/2018. On 03/02/2018 the patient experienced 2 asystolic cardiac arrests. The patient was admitted to iTU where upon retura
of spontaneous circulation on 04/02/2018 they had fixed dilated pupils, EEG performed on 05/02/2018 showed no consistent cortical activity
in keeping with severe hypoxic encephalopathy. Death confirmed 17:00 05/02/2018, The patient had no previous cardiac history and recent
ECHO and cardiac MRI were both normal. The report was recelved by the Sponsor on 05/02/2018. Cardiac arrest was assessed as related
by the site investigator to carfilzomib and was assessed by the Sponsor as unexpected for carfilzomib hence meeting the definition of a 7
day SUSAR to carfiizomlb. The trial Clinical Reviewer concurs with the site Investigator that cardiac arrest fs causally related to carfilzomib.
The clinical reviewer also assessed cardiac arrest as related to cyclophosphamide. Therefore as cardiac arrest was assessed as
unexpected for cyclophosphamide by the Sponsor, the event also meets the definition of a7 day SUSAR to cyclophosphamide. The event of
casdiac arrest was assessed as fatal on 05/02/2018, The results of a post-mortem are currently outstanding. UPDATE 49/11/2018 The
treating site now have access to the coroner's report which states cause of death as fa) bacterial bronchopneumonia, 1b) left ventricular
hypertrophy and 1c} myeloma, As 4 result of the coroner's feport's findings ‘infection - bacterlal bronchopneumoniat and ‘sepsis’ reactions
have been added to the SUSAR report. Bronchopneumonia (fatal) was assessed as related by the site investigator to carfilzomib,
cyclophosphamide and dexamethasone. Bronchopneumonia (fatal) was assessed by the Sponsor as unexpected for carfilzomlb and
dexamethasone and expected for cyclophosphamide hence meeting the definition of a SUSAR to carfilzomib and dexamethasone, Sepsis
{fatal) was assessed as related by the site investigator to carfilzomib, cyclophosphamide and dexamethasone and was assessed by the
Sponsor as unexpected for carfilzomib, cyclophosphamide and dexamethasone hence meeting the definition of a SUSAR to earfiizomib,
cyclophosphamide and dexamethasone. The trial Clinical Reviewer concurs with the site investigator that bronchopneumonia (fatal) and
sepsis (fatal) are causally related to carflizomib, cyclophosphamide and dexamethasone,

ae

| Medicines & Healthcare products
Regulatory Agency

Yours sinceraly,

7 ecior

Vigilance and Risk Management of Medicines

Submit Yellow Cards and view further information
online at www. mhra.gov.uk/yelloweard

Download the Yellow Card App for free now.
Available on iOS and Android