Andrew Cook

Coroner Dr Philip Barlow 
The Office of Her Majesty’s Coroner 
for the County of Northamptonshire 
Constabulary Block One Angel 
Square, Northampton, NN1 1ED

30 September 2021 

Dear Dr Barlow 

Reference: Mr Andrew Cook 

Medicines & Healthcare products 
Regulatory Agency 

10 South Colonnade 
Canary Wharf  
London  
E14 4PU 
United Kingdom 

gov.uk/mhra

I write with reference to your Regulation 28 letter following the inquest into the sad death of Mr Andrew 
Cook.   

Following the inquest and our report to your office dated 28 May 2021, you requested that we take 
action to prevent similar events of this kind occurring in the future.   

I have taken the opportunity to provide supporting information to the statements as well as respond to 
the request for action to be taken for each of the Matters of Concern raised. 

Matters of Concern: 
You have expressed the following matters of concern: 

Concern 1: Polyethylene Glycol (PEG) allergy is rare but may be under-reported. PEGs are ubiquitous 
and more research into their effect as allergens is required. 

Concern 2: Whether the existence, dose and molecular weight of PEG should be made clear on 
medical product information (such as the Instructions for Use, data sheets, packaging and marketing 
information). 
-

The existence of PEG in the equipment (in this case, the Sion and Sion Blue guidewires
manufactured by Asahi Intecc) was not apparent from the packaging or product information
available to the clinicians.

- PEGs are available in various molecular weights. There was expert evidence that reaction to PEG

-

may depend on the dose and exact molecular weight to which an individual is exposed.
It was acknowledged that labelling can have negative effects and therefore needs to be considered
with care. Labelling also requires coordination with other national regulators.

Concern 3: There is inconsistency and potential confusion in nomenclature. For example, PEG can be 
referred to as “Macrogol”, “polyethylene oxide” (PEO) or “polyoxyethylene” (POE). Nomenclature may 
also vary between countries. There was evidence that clinicians reviewing product information in 
urgent situations are not aware of the various synonyms.  

 
 Response to Matters of Concern 

This information should be read in combination with MHRA’s report dated 28 May 2021. 

Concern 1: general comments 
The MHRA receives approximately 20,000 medical device adverse incidents per year across a wide variety 
of issues.  In our report to HM Coroner dated 28 May 2021 we reference 10 suspected reports received 
by MHRA since 2006, including the report that was the subject of this inquest.  

Underreporting affects all types of medical devices. Underreporting can be particularly relevant to events 
involving  suspected  allergic  /  adverse  reactions.  These  types  of  event  may  be  complicated  by  several 
factors, e.g. a patient may have been exposed to more than one potential allergen from more than one 
source, one or more allergens may go unrecognised or the adverse reaction may not be immediate. 

One  major  area  of  the  MHRA’s  responsibilities  is  to  collect,  analyse,  monitor,  and  act  on  information 
relating  to  safety  concerns  from  a  range  of  data  sources  including  relevant  published  research  and 
scientific literature papers.  Whilst there has been some scientific literature produced over the last 15 years 
which has reported on PEG/macrogol exposure and its potential to elicit allergic type adverse reactions, 
the overall relative number has been very modest and limited to patient specific case studies.  Of these, 
only a few have reported clinical events potentially linked to medical device use.  

Manufacturers are required to work to keep the safety and performance of their devices under continual 
review through pro-active risk management procedure, an ongoing process of post market surveillance 
(PMS) which forms a vital phase of the device lifecycle. 

Some examples of PMS include:  Adverse incident logging, investigation  and failure analysis;  post CE-
market  clinical  trials;  user  feed-back;  device  tracking/implant  registries;  expert  user  groups  (“focus 
groups”); and literature reviews. 

Please see MHRA actions in response to this Concern. 

Concern 2: general comments  
As detailed in our report to HM Coroner dated 28 May 2021, seventeen  medical device manufacturers 
were contacted and questioned about their awareness of PEG and its association with allergy and other 
forms of adverse reaction; their post market surveillance (PMS) data; and approach used on PEG labelling. 
The majority reported having little concern regarding PEG and its potential as an allergen.  They reported 
receiving minimal adverse incident reports concerning allergy/adverse reactions and no confirmed reports 
of PEG exposure leading to adverse events. 

Nonetheless, manufacturers of such devices will often comply with relevant key designated international 
standards  to  show  they  comply  with  relevant  requirements  of  the  regulations  to  place  a  device  on  the 
market.  One  such  standard  is  ISO  14971  Medical  devices  –  Application  of  risk  management,  which 
requires the manufacturer to undertake a process of “Risk Analysis”, “Risk Evaluation” and “Risk Control”. 
In general, it requires the device (including the chosen materials) be evaluated for its safety, quality, and 
performance. It also requires that the associated Risk Management Report is updated regularly to ensure 
relevant new detail (signals) through the “real-world” clinical experience of using the device feeds into a 
risk assessment to ensure risks are minimised and the benefits outweigh these risks.  Another relevant 
key  standard  is  ISO  10993  Biological  evaluation  of  medical  devices,  which  states  that  following  risk 
analysis and evaluation and the implementation of risk controls, it is necessary to review the findings of 
these preceding activities and to document the residual risk and to decide on any further disclosure of 
such residual risks, for example through appropriate labelling, cautions or warnings. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 In general, the manufacturer is responsible for the information accompanying their medical device. This 
information should provide comprehensive, informative, and clear detail on how to use the device safely.  
Any precautions / warnings to be taken or noted before or during use of the device should be evident 
and clear.  Additional detail may be included under the “indications” and “contra-indications” sections of 
the IFU where appropriate. This is a requirement under current legislation, as well as the relevant global 
ISO standards listed above.  

Where PEG/macrogol and its derivatives are used in the forming / construction and final product of a 
medical device, where it may exist as either a major / functional ingredient or minor, trace / residue 
component or ingredient, the manufacturer should bring awareness of the presence of this chemical, as 
well as highlighting its potential as a trigger for allergy in some people, via device labelling. 

There are a number of issues relating to PEG within this case which would influence labelling 
requirements; in order to explore and understand these and ensure the labelling benefits patients and 
healthcare providers, we will engage with stakeholders to seek expert advice on the form and extent of 
the labelling needs. A range of issues will be explored including for example whether there should be 
emphasis or priority for certain types/class of device and type/risk of anticipated exposure to PEG.  

Please see MHRA actions in response to this Concern. 

Concern 3: general comments 
The variation in name / identification for PEG/macrogol seems to have evolved organically and is often 
linked to common international regional vernacular or usage with certain groups of products e.g. 
medicines, cosmetics, industrial items, as well as the particular discipline or field of interest e.g. medical, 
industrial or pure sciences (chemistry, biochemistry etc.). 

There is no specific legislative labelling requirement that instructs medical device manufacturers on how 
to decide upon the most appropriate nomenclature where more than one common name exists for an 
ingredient / chemical. 

It is likely that a manufacturer would opt for an identification that is perceived to be in common usage or 
reference (globally), however, as is the case with PEG, the situation is compounded by regional and 
subject / discipline variations. A further complication is the potential use of registered trade names 
assigned by several bulk chemical supplying industries.  

Please see MHRA actions in response to this Concern. 

PEG in medicinal products 
Whilst the product at issue is a medical device, the MHRA also regulates medicinal products and they 
were also discussed at the inquest.   

The legislation covering the labelling and packaging of medicines is a separate and different regime in 
some aspects from that in relation to medical devices. Medicines legislation recognises the need for 
excipients within a formulation to be transparent and these are listed qualitatively in the statutory product 
information for all medicines. In addition, Macrogol or PEG of various molecular weights is prevalent as a 
pharmaceutical excipient in more than 8000 medicinal products authorised in the United Kingdom. The 
nomenclature of this product is set out in the World Health Organisation of International Non-proprietary 
Names as ‘macrogol’ and this is how this excipient will appear in the medicines’ product information 
although in some cases both macrogol and PEG may be declared.   

There are guidelines on those excipients which have adverse effects in-their-own-right and the 
information which must be included. There is the separate issue of the potential for PEG to cause an 
adverse effect in-its-own-right.   The document which sets out which compounds need to be included on 
the labelling of all medicines is derived from Article 65 of Council Directive 2001/83/EC and is a 

 
 
 
 
 
 
 
 
 
 
 
 
 publication from the Commission. Macrogol (PEG) is not currently listed as an excipient of known effect.  
There are no specific warnings given in the Patient Information Leaflet on its effects 

Though the current medical device legislation does not specify the need for all ingredients to be 
named/listed, it does instruct manufacturers to label any warnings or precautions to take, as well as 
information to be given to avoid certain risks. This would include labelling those ingredients that could 
possibly induce an allergic reaction.  However, please see MHRA action points concerning medical 
device legislation under “Concern 2”. 

Actions taken or planned by the MHRA in response to the Matters of Concern 

Concern 1: 
1.  Patient safety is our highest priority. It is mandatory for manufacturers of medical devices to report 
certain  incidents  to  MHRA.    We  encourage  patients  and  healthcare  professionals  to  report  safety 
concerns  to  MHRA  through  our  voluntary  Yellow  Card  scheme.  We  run  a  number  of  campaigns  to 
promote awareness of reporting by patient, public and healthcare professionals, so that we can take 
action to help to reduce the risk of similar incidents happening again.   

2.  As part of the medical device legislation, manufacturers are required to monitor, collect, and review 
safety data on their devices in the post market phase. Through our ongoing regulatory work with UK 
Approved Bodies (UK ABs - independent assessment/certification bodies) the MHRA will continue to 
ensure that manufacturers meet their legislative obligations.  

3.  We recognise the need to raise awareness of this safety issue to patients, public and healthcare 

professionals relating to medical devices and medicines. 

-  The MHRA plan to launch a Devices Safety Information (DSI) webpage specifically on 

PEG/macrogol in medical devices to highlight its potential to illicit allergic type reactions, 
and to raise awareness of nomenclature variations. 

-  We also plan to issue a Drug Safety Update (DSU) that links directly to the DSI webpage 
(above) to reinforce this message as well as raise awareness of the different names for 
PEG compounds in medicines. 

To  further  publicise  these  safety  messages,  the  MHRA  will  utilise  relevant  patient  representative 
groups, major medical professional societies/colleges, and appropriate healthcare manufacturer trade 
associations to further publicise this safety issue.  In combination with standard alerts to subscribers 
of our safety message webpage, this will ensure a greater reach to patients, public and health care 
system. 

Concern 2: 
1.  The MHRA will work with UK ABs to communicate the importance for appropriate clear labelling with 

respect to PEG.  

2.  We will continue to engage with relevant stakeholders, in particular the medical device 

manufacturers, to develop clear guidelines on labelling requirements for PEG/macrogol. 

3.  Concerning the need for additional detail on the labelling of PEG regarding the its molecular weight 

and amount/quantity used, we will need to undertake a longer-term programme of review. The MHRA 
will discuss these points with patient representative groups, clinical experts, and industry. 

4.  The MHRA will continue to perform ongoing appraisal of the current medical devices and medicines 

UK legislation with regards to expectations on minimum labelling requirements relating to ingredients.   

On 16 September we launched a public consultation on future of medical device regulation; giving 
everyone the opportunity to contribute to the improvement of the regulatory framework and therefore 
patient safety in the future. https://www.gov.uk/government/consultations/consultation-on-the-future-
regulation-of-medical-devices-in-the-united-kingdom 

In particular – under Chapter 3 : Economic Operators (Section 6.4) : The MHRA considers that 
the UK medical devices regulations could be amended to provide further detail to the existing 

 
 
 
 
 
 
 
 
 
 essential requirements and to add further essential requirements in line with technological 
progress and international best practice to deliver public and patient safety benefits. Examples of 
how the essential requirements could be amended include: More detail on the information that 
should be provided with the medical device, including a requirement to list 
ingredients/component parts which are known allergen/sensitisers. 

5.  MHRA will seek to discuss labelling requirements with other regulators internationally, to ensure any 

future UK requirements do not adversely or significantly conflict with other global requirements that 
could compromise UK patient safety. 

6.  Where necessary and appropriate, the MHRA will communicate and share information with other 

national regulators to protect patients worldwide. 

Concern 3: 
We will review the challenges relating to nomenclature. 
1.  MHRA will engage with global stakeholders such as the World Health Organisation (WHO) and the 

International Medical Device Regulators Forum (IMDRF) on PEG nomenclature. For example, WHO 
has a “constitutional mandate to develop, establish and promote international standards with respect 
to biological, pharmaceutical and similar products" and as such manage the International Non-
proprietary Names Programme and Classification of Medical Products. The IMDRF is tasked with 
accelerating international medical device regulatory harmonization and convergence.  

2.  As described under “Concern 2”, the MHRA will discuss labelling requirements with other regulators 
internationally, to ensure any future UK requirements do not adversely or significantly conflict with 
other global requirements that could compromise UK patient safety. 

Conclusion 
The MHRA will continue to collect and review information from a range of data sources on PEG exposure 
including via our adverse incident (Yellow Card) reporting system and database, as well as independent 
scientific publications. This information will form part of an ongoing review in which we will seek views of 
external experts, that will aid us in the development of labelling advice for PEG in medical devices and 
medicines, specifically the balance of benefits and risks to patients and other users of medical devices. 

We will raise the profile of PEG/macrogol, in particular its presence in some medical devices, as well as 
associated  allergy  risks  and  nomenclature  variability,  working  with  relevant  stakeholders  where 
appropriate. 

The MHRA will appraise the feedback received from the public consultation of the UK medical devices 
legislation including the Chapter relating to labelling so that we may create a world-leading regime that 
continues to prioritise patient safety.  These actions combined with the measures above, will minimise 
risk associated with PEG allergy while ensuring continued access to devices from those patients who 
will benefit. 

Dr 
Chief Safety Officer, MHRA