Assessing and further developing age‐appropriate information for young people about reporting suspected adverse drug reactions

The Medicines and Healthcare products Regulatory Agency Yellow Card scheme (YCS) is the UK's system that collects spontaneous reports about suspected adverse drug reactions (ADRs). Reporting of suspected ADRs by young people (age <19 years) in the UK is extremely uncommon, driving efforts to improve awareness and reporting.


| INTRODUCTION
The Medicines and Healthcare products Regulatory Agency's (MHRA) Yellow Card scheme (YCS) is the UK's spontaneous reporting system that collects and monitors safety information for suspected adverse drug reactions (ADRs).More recently, suspected safety concerns other healthcare products including medical device adverse incidents, defective (not of an acceptable quality), falsified or fake healthcare products are also reportable through the YCS.There are no restrictions on who can submit a Yellow Card and the scheme relies upon the voluntary reporting.Patients, healthcare workers, parents and carers all have access to the scheme.In 2005, patients reporting (including from their representatives, e.g.parents and carers) was introduced, which lead to an increase in the number of reports, with these types of reports being as useful as those by healthcare professionals. 1,2e nature of ADRs in children and young people (CYP) are poorly captured in routine documentation and can be different to ADRs experienced by adults.These include differences in the type, severity and outcome of the reactions, whilst some ADRs are solely seen in young people (e.g.growth suppression). 3,4Prospective studies have shown that approximately 3% of all hospital admissions in CYP are directly related to an ADR, and around 20% of paediatric inpatient stays are complicated by 1 or more ADR. 3,4neral under-reporting is a known issue of spontaneous suspected ADR reporting systems.In GP Practices and hospitals in the UK there is an estimated under-reporting rate of 91% identified in English GP practices for all-type suspected ADRs in all age groups. 5ese data are derived from analysis of 15 drugs new to the market, and crucially shows that only slightly over half (27/51, 53%) of event classified as serious adverse reactions were reported, showing that even serious harms may not be reported.Whilst reporting to the MHRA YCS is voluntary for UK healthcare staff, it is supported by respective professional codes of practice, for example the GMC's Duties of a Doctor section on 'Good practice in prescribing and managing medicines and devices', and the Royal College of Nursing. 6,7In addition, there is NICE (The National Institute for Health and Care Excellence) guidance supporting reporting.Despite this, and the recognized importance of reporting, under-reporting from healthcare professionals has persisted.It must be noted that since COVID-19, numbers of general suspected ADR reporting to the YCS has increased.This is likely in part to be due to increased awareness levels through MHRA's strategic campaigns, outreach and partnership working.Patient reporting has increased since its introduction, but it is heavily skewed to adults reporting about either their own health, or on behalf of children and young people.There is extremely limited reporting by young people about suspected ADRs they have experienced themselves.Between 1 January 2008 to 29 November 2018, there were 41 630 Yellow Card reports about patients <19-year-olds, but only 948 (2.3%) of these were submitted by <19-year-olds personally rather than by parents or carers. 8This is an average of <100 reports from young people per year.This means that the reports of suspected ADRs in young people may be skewed to particular types of drug or ADR that are visible or obvious to adults, and may not reflect the drugs causing problems or the symptoms of concern to young people.
The teenage years include transition towards independence in all aspects of life, including healthcare.This is therefore a prime time for an intervention, utilizing education to empower young people to report their own suspected ADRs, and represents an exceptional opportunity for development in pharmacovigilance.
Greater awareness of the YCS in the UK amongst CYP could lead to a major increase in the number of Yellow Cards submitted annually and make strides in improving drug safety in this population.To date, the UK's National Curriculum has a Personal Social Health and Economic section, which requires CYP to have awareness of 'the dangers of drugs which are prescribed but still present serious health risks'. 9is is an excellent starting point but, crucially, the wording of the curriculum does not include informing or educating young people about what actions they could take in the event they are concerned about a suspected ADR and reporting to the YCS, however it does include a link to the YCS reporting website in the teachers' notes.• Of the reports received, the quality of reports is good, and different but important drug/reaction pairs are submitted when compared to adults reporting about young people.
• Efforts to educate on this topic are necessary to increase reporting rates.

What this study adds
• Age-appropriate information that was developed in collaboration with young people was well-received, and the young people reported both a high level of comprehension as well as increased willingness to report suspected adverse drug reactions in the future.
• Using this age-appropriate information, young people included in the survey were able to identify 307 drugevent combinations, more than the MHRA normally receive in a year.the help of >300 CYP, the MHRA pharmacovigilance team and paediatric pharmacologists, which was then tested via survey with >200 CYP participating to quantify its efficacy and receive feedback for its improvement. 8,10Results showed that the guide increased in knowledge and confidence to report, but significant graphic design improvement was required, which has now been undertaken.There were also concerns about how representative the population of young people who participated in the survey were.This project therefore aimed to undertake an anonymous quality improvement project to test the finalized guide (Figure 1) on a much larger and more representative group of young people, to determine if any final developments were required prior to working towards implementation.

| Quality improvement project
This project followed the same methodology as a previous quality improvement project that collected anonymous information about young people's opinions on specific information, for the purpose of  S1), which included a QR code to access the questions via Microsoft Forms, and were asked to complete an audit providing demographic information about their school/ college (supplementary data section Figure S2).The QR code on the poster granted access to the survey on Microsoft Forms.No personally identifiable information was collected and no personal medical questions were asked.Participation in the survey was limited to those age 13-18 years old, adhering to General Data Protection and Regulation (GDPR) legislation.The full survey is in the supplementary data section (Figure S3).All remaining data were analysed using descriptive statistics (Microsoft Excel).
RAs were also included in reviews of the draft manuscript, providing meaningful feedback on content and message.

| RESULTS
Twenty-one schools participated and produced survey results.Demographics of these schools are seen in were 810 respondents (27.9%) currently taking medicines, and 2814 (91.9%) have taken or been given medicines before.In total, 2860 (93.6%) of the young people had heard of side effects before, with 1113 (38.1%) believing they had experienced a side effect to a medicine.Of these 1113, 36 (2.5%) stated that their side effect was 'Very serious-bad enough to go to hospital'.Seventy (4.9%) described their suspected ADR as 'Somewhat serious-bad enough to see a healthcare professional such as their GP'.
A steady increase in the number of respondents currently taking medicines is present from 13 to 18 years old, with 94 (24%) 13-yearolds taking medicines, vs. 54 (33.5%) 18-year-olds.A similar increase with increasing age can be seen in the number of respondents who had heard of side effects, with 344 (87.9%) of 13-year-olds having knowledge of side effects, increasing with age up to 152 (94.4%) of 18-year-olds.This pattern was also observed for those who believed that they had experienced a side effect before of any severity, with 127 (32.4%) of 13-year-olds saying they had, increasing with each year to 77 (47.8%) 18-year-olds saying they had.Details of percentages responding to these questions are shown in the supplementary data section (Table S1).
An optional question for respondents who reported having a suspected ADRs in the past asked them for the drug-reactions pair; T A B L E 2 Questions and responses from the 2933 young people who undertook the survey, and their knowledge and experiences of side effects.viding both drug and reaction.These 307 drug-reaction pairs are listed in supplementary material section (Table S2) and have been provided to the MHRA Pharmacovigilance team.The 10 most common drugs suspected of causing ADRs in respondents are shown in Table 3, along with the suspected reactions (in their own words).When compared to previously published data on Yellow cards reported about young people to the MHRA, none of the top 10 most commonly reported medications suspected in our cohort (Table 3) were included in the top 10 reported about young people, and only comprised 4 of the top 20.
There were 184 (6.3%) young people who reported having heard of the YCS before completing the survey, and 23 (0.8%) that they had completed a Yellow Card report previously.Prior to reading the updated guide participants were asked 'How comfortable would you be to report a side effect?', with 384 (13.3%) recording 'Not comfortable'.After reading the guide this decreased to 117 (4.1%), a >3-fold decrease (Figure S4), which was statistically significant (P < .000001 Similarly, when asked 'Whom would you tell if you thought you had a side effect to a medicine?Select all that apply', responses changed from before reading the guide to afterwards.Before reading, 307 (9.4%) selected either 'I would report a Yellow Card myself' or 'All of the above', but afterwards this increased to 1561 (55.1%), a nearly 6-fold increase.
In total, 2709 (92.8%) of the young people who responded reported that they understood the updated guide, and 2562 (90.8%) said they know more about side effects after reading.Regarding young people's willingness to report a side effect in the future, 2383 (84.5%) of responders said they would report an ADR in the future, 13.2% said they were 'Not sure' (Figure S5).S3).
Responses are displayed here: • Nothing could be improved or words to that effect (n = 689, 33.1%).Increased from 22.6% from previous iteration. 10Content, or length of the text could be altered in some way (n = 543, 26.1%).Decreased from 35% in the previous survey. 10Graphic design could be improved: (n = 357, 17.2%).Decreased from 29.9% in the previous survey.For the full data set of answers to this question, see Table S4.
When asked where and how the guide should be distributed so young people could see it, 2069 young people responded, with the most common answers being schools and social media.Other answers included 'online' and 'posters'.

| DISCUSSION
The Alder Hey Research Ambassador programme, delivering the Yellow Card information quality improvement project, has managed to obtain responses from nearly 3000 young people nationally, generating 1 of the largest datasets regarding young people with regard to pharmacovigilance education.It has identified that young people believe they have experienced a large number of suspected ADRs, with a significant proportion being significant enough to warrant review by healthcare professionals, and the guide in its current form delivers information in a way that is understandable to the young people.In addition, it shows the depth of under-reporting, as there is only an average of about 100 Yellow Card reports directly from young people each year in the UK, and this survey alone identified 307 drug-reaction pairs, >3 times this number.
If information is developed for a particular group, then it is essential that it is tested on as representative a range of that population as possible.Whilst the development of the text, and subsequent testing in previous studies has included over 600 young people, there were concerns that the previous survey may not have had enough respondents to be sufficient, and the population recruited may not have been representative.This work has increased the number of respondents >10-fold 10 and has used school pupils who are not associated with hospitals or health services, which provides some reassurance that they are more likely to be representative of the general population.The proportion of UK teenagers using medicines is approximately 40-50% 12 but this includes 1-off prescriptions, so the prevalence of regular prescriptions (30%) in our cohort, whilst lower, seems reasonable.
However, the anonymous nature of the responses precludes any more detailed understanding of the young people who responded, but the nature of responses was broadly similar to the previous survey; the most common age in the 2022 paper was also 14, and 93.8% of CYP had heard of side effects compared to 93.6% in this survey.
In addition, very similar numbers believed they had experienced a side effect before (35.1% previously vs. 38.1% now).A greater percentage in the previous survey deemed their suspected ADR as 'very serious-bad enough to go hospital' in 4.9% compared to 2.5% in this cohort, and a greater percentage reported having heard of the YCS previously (3.6% in the previous survey vs. 6.3% in this), which was unexpected.
However, there are limitations to the project, firstly regarding school demographics.There is a higher proportion of pupils at independent schools compared to state schools in our cohort compared to the national proportion.Nationally, 6.5% of all students are privately educated, whilst in our cohort 19% were private schools, and these pupils provided 690 responses (23.5%). 11There was also a higher proportion of selective (grammar) schools in our cohort, com- What is already known about this subject• Young people aged <19 years are allowed to submit reports of suspected adverse drug reactions to the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme, but very few are completed.
Schools were recruited to the inaugural Alder Hey Research Ambassador Programme, which aims to recruit individual pupils from a range of secondary schools and colleges nationally.Schools were asked to nominate a link member of staff, and identify their prospective Research Ambassador (RA), usually from year 12 (aged between 16-17 years).In return for helping with the delivery and promotion of the survey, the RAs have been provided training (1:1 sessions via Zoom) and experience in data handling and analysis, prioritized for work experience placements within the hospital research division, and have meaningfully contributed to the writing of this manuscript and received formal acknowledgement as authors, providing significant incentives for those interested in STEM (Science, Technology, Engineering and Mathematics) careers.The Alder Hey Research Ambassador Programme will be undertaken annually, and is open to any interested UK secondary school.The school receives individual school level feedback related to the curriculum to help deliver sessions for their students.

F I G U R E 1
Finalized information leaflet produced for educating Children and Young People on their suspected adverse drug reactions (ADRs).enhancing this information.The quality improvement project was registered with Alder Hey Children's Hospital audit department. 10From 31 November 2022 to 15 February 2023, 22 schools were identified, and 21 proceeded to recruitment.Schools were recruited through methods including: connections made in previous projects, advertisement of the research Ambassador Scheme on platforms such as Twitter and LinkedIn, direct approaches to schools in the local area of the hospital via email, and use of friends and family school contacts.RA training was undertaken from 19 November 2022 to 28 February 2023.RAs were provided with the poster for survey promotion (supplementary data section Figure The survey was distributed in the first school on 28 November 2022, and the last school on 6 March 2023.The survey was closed in the first school on 27 February 2023 and in the last school on 8 April 2023.Once the survey was discontinued at their school, RA's were given their school's quantitative sections of results and provided with the educational resources to help them analyse the data and provide sums of survey responses for each question.
To continue the iterative improvement of the guide, questions with free text responses were provided to ascertain 'What did you like about the guide?' and 'What could be improved' (about the guide).Word clouds were generated to visualize the most common responses, and to indicate which words to search the responses for in Microsoft Excel when analysing the responses to allow categorization of themes, given the size of the data set (Figure 2A,B).The keywords searched for in the data set are shown in supplementary data section, as well as the full text of the responses (Table S2).The question about what was liked about the guide received 2386 responses (81.4%).These responses were represented in a word cloud (Figure 2A).Common themes included: Informative, easy to understand, colourful, clear, simple, learnt about the YCS.Regarding areas for improvement, 2080 (70.9%) answered (Figure 2B).There were thematically categorized, with seven F I G U R E 2 Word clouds generated using Free Word Cloud Generator to find common themes in responses to (A) question 16 'What did you like about the guide?' and (B) question 17 'What could be improved' (about the guide). 11categories emerging: Nothing/I do not know, improve the graphic design/how it looks; altering the text/content; requests for examples of specific drug-reaction pairs; add more pictures/diagrams; create versions for younger readers/more accessible (Table

prising 9
of the 17 state schools, when overall in England only about 5% of secondary pupils attend this type of school.Part of the reason for this may lie in the proximity of the Wirral, and parts of Manchester, to the base hospital, as they are areas of England that continue to run selective secondary education.This is reinforced by the geographical spread of the schools, with 18/21 schools being in the northwest of England, 17 of these in Merseyside.Only 3 schools lie outside of the northwest, all of which are in the southeast (Surrey, East Sussex and Kent).Looking to the next iteration of the RA scheme, additional work will need to be done to increase the number of schools that are neither selective nor private, to ensure that as representative population of young people as possible is able to participate.Moving forwards, whilst iterative improvement of a guide such at this will need to be considered on an ongoing basis, the next key step is to work towards implementation into schools.If the goal of a change in the national curriculum achieved or fully adopted through allied lessons being taught to support children and young people, for example personal, social, health and economic education, then this information would reach up to 750 000 young people in the UK every year, massively increasing the pool of potential reporters to the Yellow Card scheme, and increasing the knowledge and skills of young people about medicines as they transition into adult life and ultimately their future reports helping to improving the safe use of healthcare products and patient safety.

Table 1 ,
listed in chronological order of recruitment to the RA scheme.Ten single-sex schools were recruited (6 girls', 4 boys' schools) and 11 mixed schools.There were 17 state schools and 4 private schools.Of the state schools, 8 did not have selection criteria, 9 did including 11+ examinations and religious affiliation.From 15 November 2022 to 8 April 2023, the survey received 2933 valid responses which were included in the analysis.Demographics of the survey responders are shown in Table 2.The mode age of respondents was 14 years with 671 responders (22.9%).There T A B L E 1 Demographics and survey participation from schools participating in the 2022-23 Alder Hey Research Ambassador Scheme.
The 10 most reported drugs causing drug-reaction pairs in question 7, with examples of reported reactions.There can be >1 suspected reaction per medication.