Carl Schmidt

UNIVERSITyDF 
BIRMINGHAM 

COLLEGE OF MEDICAL 
AND DENTAL SCIENCES 

Pmfessor 
MD  FRCP FMedSci 
Pro-Vice-Chancellor 
Head of College 
Dean of Medicine 

06 November 2019 

Confidential 

Your ref: KMcL/JN/16191 

Our ref : 559/DHA/JS 

Kevin  Mcloughlin 
Office of the Senior Coroner 
West Yorkshire ( East) 
Coroner' s Office and Court 
71 Northgate 
Wakefield 
WFl 38S 

Dear Mr Mcloughlin 

Inquest touching t he death of Carl Anthony Schmidt 
Response to Regulation 28 Report 

Thank  you  for  your  letter  of 11th  Septem~ 
r  Regulation  28  Report  and  other 
enclosures  as  listed, addressed  to  Professorlllllllllllllll We  are  also  in  receipt of a copy of 
of 10t h  October  2019.  Please  take  th is letter  as  the 
your subsequent  letter to  Professor -
formal response of the University of Birmingham ('the University') to your above Report. 

We  do not have  the contact details for Mr Schmidt' s family and so  have  not been  able to write to 
them  to  express  our sadness at his death. At the outset therefore, we would  be very grateful if you 
could  pass  on  to them our sincere condolences. We are very conscious that as the anniversary of his 
death approaches, t his will be a particularly difficult time for them . 

Background 

The  University of Birmingham  is committed  to  maintaining  the  highest standards of scholarly and 
scientific integrity in its research. It expects everyone working under the auspices of the University of 
Birmingham to work to  these  standards and  clinical trials have  been  undertaken at and  through the 
University for many years. 

As  one  of the  largest  centres  for clinical  trials  in  the country, the University is  fully  committed  to 
transparency and  public accountability. It is central to our co re  mission to generate new knowledge 
through research, including working closely wit h healthcare providers all over the world . 

15 2TT  United Kingdom 

w:  www.birmingham.ac.uk 

 2 

One  of the  two  clinical  trials  units at the  University  is  the  Cancer  Resea rch  UK  Clinical  Trials  Unit 
(CRCTU), which has been in existence for some 36 years and is one of the largest clinical trials units in 
the UK. It is a specialist research unit with remit  to design, conduct, analyse, and publish investigator-
led and initiated clinica l t rials in cancer. It aims to translate cutting-edge science into improved patient 
care,  rapidly,  and  safely,  through  the  design  and  conduct  of  large  multi-centre  international 
randomised trials as  well as smaller Phase 1 trials o f novel therapies. 

We have outlined below the trial specific information for the 'Com pARE' trial (the Trial) in  relation to 
the  trial  specific  ethics  and  integrity  information,  with  the  aim  of providing  assurance  about 
participant safety and the data integrity mechanism in place for t his Trial. Brief details about the aims 
of the Trial are also attached as Appendi><  1. 

The  University is  the Sponsor of this Trial which means that  it is ultimately responsible for initiating, 
managing  and  financing  (or  arranging  the  financing)  of the  research.  The  Tria l  is  run  through  the 
University's CRCTU  and  on a  day  to  day  basis,  it is  managed  by  Professor -
as  the  Chief 
Investigator, in conjunction with the team  in the CRCTU . 

Cancer  Research  UK  funded  the CompARE Trial and  in  line with the  usua l funder review  processes, 
the funder undertook an  independent scientific review, where  experts recommend  the  project for 
fundin g, as it addresses a gap in the evidence with an appropriate methodology. 

Sponsor  due  diligence  is  undertaken  during  the  trial  set-up  period,  where  trial  documentation  is 
reviewed  internally by our Research  Governance Team  prior to  subm ission to independent research 
ethics  committees  and  regulators.  In  t he  UK,  this  is  a  national  function  carried  out  by  the  NHS 
Research  Ethics  Committee  (REC),  now  operating  under  the  Health  Research  Authority  and  the 
Medicines and  Healthcare products Regulatory Agency  (MHRA) . A favourable opinion from NHS REC 
was  received  on  the  27  November  2014  and  regulatory  MHRA  approval  was  received  on  the  12 
January 2015. 

In  addition,  the  University's  Clinical  Trials Oversight Committee  (CTOC),  provides  oversight  to  all 
clinical trials undertaken at the University. 

The Trial has a Trial Management Group (TMG), which includes co-investigators from the sites around 
the  country that  are involved  In delivering  the study and several head  and  neck medical oncology 
specialists and  radiothera py specialists  from  around  the  UK.  The TMG  meets approximately every 3 
months although  members are  in  regular contact between mee tings. 

The  Trial  also  has  an  independent  Data  Monitoring Committee  (DMC)  - an  independent  gro up  of 
experts  established  to  monitor  patient  safety  and  the  statistical  integrity  of the  Trial  while  it is 
ongoing. The DMC meets every 6-12 months but also receives monthly recruitment figures. Members 
of the DMC  are  independen t  of the  Tria l,  the  University,  and  t he  hospital  and  clinician  where  the 
patient  was  treated .  For  CompARE,  the  DMC  com prises  an  experienced  world-leading statistician 
(chair),  an internationally renowned head and  neck radiation oncology expert and an internationally 
renowned head and  neck surgeon. 

Since  the Trial  opened  to recruitment in July 2015,  318 patients have  bee n recruited  in numerous 
sites around the country, including 88 recruited into Arm 3 (dose esca lated radiotherapy). Mr Schmidt 
signed up for the Trial in February 2018 following diagnosis for cancer of t he tonsi ls.  He was provided 
with the necessary  Patient Information Sheet and  signed  the Trial consent forms for registration to 
the Trial  and w as  randomised  (entered into the Trial) on 20th  February 2018.  He received treatment 
under Arm 3 of the Trial between P' March and 5 th April 2018. 

Birmingham  B 15 ]TT  United Kingdom 

www.medicine.bham .ac.uk 

 3 

Action post Inquest 

The CRCTU  was  notified of the deat h of Mr Schmidt  by  the Trial site at Leeds on 10t h  January 2019, 
who reported that the cause  of death was  then unknown. It is  not uncommon fo r patients t o die in 
ca ncer  t rials  due  to  the  life-threaten ing  nature  of the  disease  and,  having  reviewed  the  history 
provided,  t his was assessed  in  line w ith protocol  definitions  as  not  requiring particular exceptional 
action at that time. 

A Suspected  Unexpected Serious Adverse Reaction (SUSAR) was submitted to MHRA on the 51h  April 
2019  in  line  with  regulatory  expectations,  after the Sponsor  was  made  aware of  the patient's full 
presentation on t he 29th  March  2019. 

h  September.  As  the  Chief  Investigator,  Professor  -

The  CRCTU  was  notified  of the  outcome  of  the  subsequent  inquest  by  the Trial  site  at  St  James' 
Institute  of  Oncology  Leeds  on  9t h  September  2019.  This  was  a  fe w  days  prior  to  receipt  of the 
Regulation  28  Report  dated  111
immediately reviewed the situation with CRCTU  and on 12th Sept ember 2019 arranged suspension of 
recruitment  into  Arm  3  o f  the  Trial  pending  further  investigation  being  undertaken  around  the 
circumstances of the  death  of the  patient.  He  notified  t he  TMG  who  w ere  in  agreement  and  he 
informed the chair of the  DMC. The  MHRA were  sent a follow up SUSAR  report on 12t h  September 
and were notified of t he suspension by te lephone on 13t h September and in writ ing on 16th September 
2019. At the da te of this Response, recruitme nt continues to be suspended. 

Subsequent review of the Trial by the University 

In  the  light of the outcome of the Inquest and  receipt by Professor -
Report , a number of act ions were  undertaken to review the activity under the Trial. 

of the Regulation  28 

a) 

t he  clinician  who  t reated  t he  patient at St James'  Institut e of Oncology, 

provided both the dosage plan and the radiothera py outlining pla ns (CT scans)  for review. 

b)  The  radiotherapy outlining plans and  the radiotherapy  doses for t he patient were reviewed 
by  the  TMG,  independent of-
These  showed  that  the only  peripheral  nerves  that 
received the experimental higher dose were the right CS nerve root of the brachia I plexus and 
right recurrent  laryngea l  nerve .  The  rest of the  brachia!  plexus  on  the  right,  and  the left 
brachia!  plexus,  and  the  cranial  nerves, brain  and  spinal  cord  all  received  doses  within the 
internationally  accepted  tolerance doses  delivered  by  normal,  routi nely-used  radiotherapy 
doses  (i.e.  within  standard  limits  of  rad iotherapy  doses  used  normally)  and  not  the 
experimental higher dose. 

-
~ 

c)  The  two  pathologists  who  carried  out  the  ~ 

for further information.  These  wer~ 

re  contacted  by  Professor 
general pathologist) 

-

pathologist stated that his conclusions were based on the results of 

Consulta nt Neuropathologist)-copies of their correspondence are attached as 
the  general 
As  you  can  see  from  the  informat io n  provided, 
conclusions as 
is  not a  specialist  neuropathologist.  As  can  also  be  seen,  having  received  the 
additional  information,  t he  neuropathologist, -
now  considers  it  less  likely  that 
radiotherapy  effect  was the  cau se  of patient' s polyneuropathy  because  the  experimental 
higher dose of radiotherapy was on the right side only but the symptoms of polyneuropathy 
were bilateral. 

d)  Following and  in  the light of the pathologist s'  input,  an emergency meeting of the DMC for 

the Trial was convened. 

Birmingham  B 15 2TT  United Kingdom 
www.medicine.bham.ac.uk 

 4 

The  DMC  (and  notably  the  radiotherapy  oncology  expert)  reviewed  all  the  available 
information (both the dosage plan and the radiotherapy outlining plan) and did not conclude 
that the patient's symptoms or death were caused  by direct damage from the radiotherapy 
on  the  local  peripheral  nerves.  The  reason  for this  is  that the patient  had  polyneuropathy 
bilaterally  including  contralateral  (left)  arm  and  bilateral  vocal  cord  palsy  (i.e.  including 
contralateral  recurrent laryngeal  nerve),  whereas  the  high dose  radiotherapy only affected 
the right recurrent laryngeal nerve and t he right CS root. 

The  DMC  concluded  that  whilst  the  possibility  of an  indirect  immune  response  due  to 
radiotherapy cannot  be completely excluded, to their knowledge,  this  'abscopal'  effect has 
only been described for tumour tissue, and not normal tissue, including neurological t issue. 

Based on  the 1nformat ion available to the DMC,  it is believed that a more likely cause of death could 
be cisplatin neuropathy (well documented for patients  receiving the standard dose of cisplatin that 
this patient received), alcoholic neuropathy (the patient reported  drinking 120 units per week}, or a 
virally-mediated condition such as  Guillain Barre syndrome, or a combination of the above. 

Conclusion 

We  fully  appreciate  that  the  conclusion  reached  at the  Inquest was  made  on  the  basis  of the 
information  available  to  you  at  the  time  of  the  Inquest.  However,  in  light  of the  subsequent 
information and review above, we hope you will agree that there are reasonable grounds to question 
the  balance  of 
whether  the  conclusion  reached 
probability.. .. .radiotherapy induced nerve injury was the likely mechanism of his death ..... ". We would 
be grat ef ul to know  whether you  consider that these  are  circumstances  where it is  appropriate  to 
apply for a note to be added to the patient's death certificate. 

remains  appropriate,  namely  that  " .... on 

3.  Moreover,  a  previous  study  which  concluded 

The University is not aware that there have been other similar clinical outcomes to patients receiving 
2015 
treatment  under  Arm 
https :1/www.cancerresea rch uk.o rg/about-cancer /fi hd-a-clin ica 1-tria I/a-study-loo king-i ncreasing-
( the  ART  DECO 
dose-radiothera py-treat-cance r-vo ice-box-or-lower-pa rt-of-the-throat-art -deco 
study)  delivered  a biologically similar radiotherapy dose  to  that  of  Arm  3 of CompARE. That  study 
recruited  276 pat ients and (to t he  best of Professor ~ 
nowledge and  that of the TMG) did 
not result in similar adverse events. Therefore discontinuation of this treatment arm within the Trial 
could therefore potentially deprive future patients of the treatment afforded by the Trial. 

in 

The  University has thoroughly reviewed the risk mitigation processes and  ope ration of the Trial, the 
treatment provided,  the potentia l benefit to patients, and the circumstances of th is particular case. 
For the reasons  mentioned above, the  University does  not believe that the experimental t reatment 
given  in  Arm  3  is  likely  to have  been  the  cause  of death.  Accordingly,  and  as  the  review  has  not 
identified  reasons  for continued suspension  of Arm  3,  the University (in consultation w ith the TMG 
and DMC)  believes that resumption of recruitment into Arm 3 would be justified . 

Yours sincerely 

Pro essor 
Pro-Vice Chancellor 
Head of College of Med'ical & Dental Sciences 
for and on behalf of  the University of Birmingham 

Birmin oham  B 15 2TT  United Kingdom 

www.medicine.bham.ac.uk 

 5 

APPENDIX 1 

CompARE Trial - Summary 

Patients  with  intermediate-risk  and  high-risk  oropharyngeal cancer (OPC)  respond  less  well  to the 
standard t reatment and have  a much worse outcome than low-risk OPC.  New treatment paradigms 
are  being considered for bot h  intermediate and high-risk OPC which are more  resistant to standard 
treatment.  The  purpose  of  the  CompARE  trial  is  to  test  several  alternative  regimen s  for  the 
intensification  of curative  treatment  for  patients w ith  intermediate-risk  and  high-risk  OPC.  These 
regimens involve intensifying current standard of care by the intensification of the chemotherapy or 
radiotherapy components or the addition of surgery or immunotherapy. 

The aims of the CompARE Trial  are as follows: 

1.  To  examine  the  outcomes  of  alternative  treatments  aiming  to  improve  overall  survival  in 
intermediate and high-risk OPC 

2. To  compare Quality of Life  (Qol), toxicity outcomes and  swallowing function of these  alternative 
treatments 

The CompARE Trial opened to recruitment on  6th July 2015 at the Queen Elizabeth Hospital. The first 
patient was randomised on 17th July 2015.  Initially, three arms opened to recru itment: 

Arm 1: Concomitant cisplatin chemotherapy plus radiotherapy 
Concomitant chemoradiotherapy, 3-weekly  cisplatin  100mg/m2 or weekly  40mg/m2 w ith  Intensity 
Modulated  Radiotherapy  (IMRT}  using  70Gy in  35F  +/- neck  dissection  as  indicated  by clinical and 
radiological  assessment  3-months  post  treatment.  This  is  the  international  gold  standard. 
Radiotherapy will  be  delivered  using  IMRT (70Gy  in 3SF}  over 7  weeks to  the primary tumour and 

lymph node metastases 

Arm 2: Induction chemotherapy followed by arm 1 
Induction chemotherapy (3 cycles at 3-weekly intervals: Docetaxel 75mg/m 2 + Cisplatin 80mg/m1 + 5-
Fluorouracil (5-FU) 800mg/m2/day, daily for 4 days), followed by arm 1. 

Arm 3: Dose-escalated radiotherapy plus concomitant cisplatin 
Dose-escalated  chemoradiotherapy  using  intensity  modulated  radio therapy  (IMRT)  64Gy  in  2SF  + 
Cisplatin  100mg/m2  day 1 of week 1  and of week 5 or weekly 40mg/m 2
.  Neck dissection as  indicated 
by clinical and  radiological assessment at 3-months post-treatment. 

Removal and addition of trial arms 
Due  to  the  multi-arm  multi-stage  (MAMs)  design  of the  trial,  arms  can  be  added  or removed  as 
deemed necessary. Arm 2 closed to recruitment on 9th January 20 17. Arm 4 of the trial (Resection of 
primary followed by arm 1) opened on 6th  March 2017, but later closect on 71

~  February 20 19. 

Arm S opened to recruitment on  2nd October 2017. 

Arm 5:  Induction durvalumab plus arm 1 and  then adjuvant durvalumab 
One dose of induction durvalumab 1500mg by intravenous (IV) infusion followed by arm 1 within four 
w eeks.  Within one-two weeks -after the completion of arm  1, durvalumab 1500mg every four weeks 
will be initiated for a total of 6 months. 

Bim1ingham  81 5 2TT  United Kingdom 

www.medicine.bham.ac.uk 

 APPENDIX 2 

athologists: 

19 September 2019 
9 Sept ember 2019 

6 

Birmingham  B15 2Tf  United Kingdom 

www.medicine.bham.ac.uk 

 The Mid Yorkshire Hospitals rr/:fj 

NHS  Trust 

Bringing together community and hospital services 

Department of Histopathology 
Dewsbury &  District Hospital 
Halifax Road 
Oewsbury 
West Yorkshire 
WF134HS 

Tel: Hospital0844 811  8110 

Email : 

Enquiries  to: 

Ex te - - ·  

Direct Dial:

Our Ref: PB/RAH 

19/09/2019 

Professor 
Institute of Head and Neck Studies and Education 
School of Cancer Sciences 
University of Birmingham 
Birmingham 
B15 2TT 

Dear Professor 

Re:  Urgent Request for further information regarding  CompARE Trial patient 
TNO 168 (inquest date 5th September 2019, West Yorkshire Coroner's Court) 

Thank you for your letter, dated 19th  September 2019.  I am  more than happy to  assist 
you  with  the  queries  you  have  raised. 
I  can  confirm  I  performed  the  post-mortem 
examination  of  patient  CS  on  the  29th  November  2018.  My  examination  did  not 
include gross  and  mic~ ion of the  brai n and  spinal cord  - these were 
fixed  and  referred  to - - - - Consultant  Neuropathologist  at  St  James's 
University Hospital in Leeds. 

This was a challenging  post-mortem case, and  I did  hear new evidence  at inquest that 
raised  uncertainties over the mechanism  of death in this case, particularly with regards 
to how the  radiotherapy was delivered. 

To address your questions in order: 

The basis on which you concluded that the symptoms were caused by radiotherapy? 

The  history  provided  prior to post-mortem  indicated  a  relatively  slow progression  (3-4 
months)  of symptoms  that  apoeared  temporally  related  to  radiotherapy  treatment. 
This  concern  was  also  raised  clinically.  I considered  other  causes, such  as Guillain-
Barre  syndrome,  but  considered  at  this  time  that  the  onset  of symptoms  was  too 
gradual.  At inquest, further evidence indicated  that it was a  little  more uncertain as  to 

Gb
@·: 

UK AS 

M(Pl(.Al 

Chairman - Jules Preston MBE 

9026 
An  Associated Teaching Trust 

Chief Executive - Martin Barkley 

 how long  symptoms  had  actually persisted  for;  ultimately  meaning  that  Guillain-Barre 
could  not be completely excluded. 

-

opinion  was  ultimately  that the  cause  of the  neurological  symptoms  was 
likely to  be  radiotherapy effect on  local  cranial  and  spinal  nerves.  As  I had  not found 
any other significant pathology to  account for the symptoms  I considered  that this was, 
on the  balance of probability, the most likely mechanism of death in  this case. 

Were  there  any  histopatho/ogical  changes  in  tenns  of  necrosis,  apoptosis  or 
demyelination or any other son in  the bu/bar region  of the  brain  or in the  spinal cord 
that would suggest damage caused by radiotherapy?  Was there inflammation present? 

(LA18-1277) would suggest not.  I would advise approaching 
The report from -
him  for  further  advice  in  this  regard ,  as  neuropathology  lies  outside  of  my  area  of 
expertise. 

Do you know if alternative  causes, including Guillain-Ba"e, were e,cc/uded? It would be 
helpful  to  know  if additional tests  such  as CSF analysis,  EMG  and nerve  conduction 
tests were performed and considered. 

Please  see  the  comment  above  regarding  Guillain-Barre.  The  hospital  records 
indicate  one  CSF  sample  was  taken.  This showed  clear colourless fluid , negative for 
culture.  with  white  blood  cells  <1  x  106/L  and  red  blood  cells  9  x  106
I  am  not 
certain  if EMG  or  nerve function tests were taken  - I have  re-reviewed  the  electronic 
clinic records  and  cannot find any evidence of these  investigations being  performed. 

/L. 

The  outcome  of the  inquest  was  that  of uncertainty  and  this  was  acknowledged  in 
court.  HM  Coroner ultimately favoured  radiotherapy  as a contributing  factor based on 
the temporal  link between the  patient's symptoms  and the onset of treatment, and also 
based on the  report provided b)-

1hope this  is of some use to you.  Please do not hesitate to  contact me if you  require 
further information. 

Yours sincerely 

Consultant Histopathologist