Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol

Supportive care; palliative care; medicines optimisation; pharmacogenomics; pharmacogenetics ALL Metrics - Views Downloads How to cite this article Patel M, McDermott J, Newman W and Barry C. Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.14182.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Study Protocol [version 1; peer review: 2 approved with reservations] Martyn Patel https://orcid.org/0000-0002-9313-3894 1,2, John McDermott3,4, William Newman3,4, Caroline Barry1,2Martyn Patel https://orcid.org/0000-0002-9313-3894 1,2, John McDermott3,4, William Newman3,4, Caroline Barry1,2 PUBLISHED 22 Dec 2025 Author details Author details 1 Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England, UK 2 University of East Anglia Norwich Medical School, Norwich, England, UK 3 Manchester University NHS Foundation Trust, Manchester Centre for Genomic Medicine, Manchester, England, UK 4 Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, England, UK 2 University of East Anglia Norwich Medical School, Norwich, England, UK 3 Manchester University NHS Foundation Trust, Manchester Centre for Genomic Medicine, Manchester, England, UK 4 Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, England, UK Martyn Patel Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing John McDermott Roles: Methodology, Project Administration, Resources, Visualization, Writing – Review & Editing Roles: Methodology, Project Administration, Resources, Visualization, Writing – Review & Editing William Newman Roles: Methodology, Supervision, Writing – Review & Editing Roles: Methodology, Supervision, Writing – Review & Editing Caroline Barry Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS People living with life limiting conditions such as incurable cancer often have problems with pain, vomiting and other symptoms which impact quality of life. Supportive and Palliative Care aims to improve people’s symptoms, particularly towards the very end of life. Many medications exist that can be used to help with these symptoms, but often they do not work, or they cause side effects for the people taking them. “Pharmacogenomics” is a way of predicting who is more likely to have a good response to drugs, and who is more likely to get side effects, based on variation in their genes. A prospective observational study, recruiting 50 patients aged over 18, with life limiting conditions. The study aims to understand how the introduction of multi-gene pharmacogenetic test for patients receiving palliative and supportive care might impact routine prescribing practice in an acute NHS hospital setting. It will report on the nature of prescribing patterns over a 90-day period post recruitment, looking for any variation between patients with and without the presence of actionable drug-gene interactions. It will help determine the future feasibility of incorporating pharmacogenomic testing in a palliative care population based on recruitment targets versus actual recruitment achieved. A drug-gene interaction ratio for this cohort will be reported, giving an indication of the scale of the use of medications relevant to pharmacogenomics used in palliative care, and the potential scope of future interventions. The study involves the collection of a single blood sample, and genetic results will not be shared with participants. This single site study aims to provide preliminary data to inform study design of clinical trials that can definitively address the question of clinical utility in this population, whilst also understanding the acceptability of researching this topic in this specific patient population. ClinicalTrials.gov ID NCT06856122, registered 2025-03-04 People living with terminal or life limiting conditions such as incurable cancer often have problems with pain, vomiting and other symptoms which impact quality of life. Supportive and Palliative Care aims to improve the symptoms of people with terminal conditions, particularly towards the very end of life. There are many drugs that can be used to help with these symptoms, but often they do not work, or they cause side effects for the people taking them. “Pharmacogenomics” is a way of predicting who is more likely to have a good response to drugs, and who is more likely to get side effects, based on their genes. We know that changes in certain genes (as happens naturally in the population) might mean that a drug might not work as well for some people as others. We are interested in whether testing for these differences in genes for people living with cancer and experiencing symptoms, might help improve their care, and how to provide feedback from these test results to the clinicians involved in patient care. Supportive care; palliative care; medicines optimisation; pharmacogenomics; pharmacogenetics Corresponding Author(s) Grant information: This project is funded by the National Institute for Health Research (NIHR) under its Biomedical Research Centre (BRC) Programme (Grant Reference Number NIHR 203956)]. This project is also funded by the National Institute for Health Research (NIHR) under its Research Career Funding - Doctoral Fellowship (DRF) Programme (Grant Reference Number NIHR 301748). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was funded by the NHS England Genomics Programme through the Pharmacogenetics and Medicines Optimisation Network of Excellence. Additionally, JHM and WN are supported by Innovate UK (10058536). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2025 Patel M et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Patel M, McDermott J, Newman W and Barry C. Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.14182.1) First published: 22 Dec 2025, 5:125 (https://doi.org/10.3310/nihropenres.14182.1) Latest published: 10 Apr 2026, 5:125 (https://doi.org/10.3310/nihropenres.14182.2) The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was funded by the NHS England Genomics Programme through the Pharmacogenetics and Medicines Optimisation Network of Excellence. Additionally, JHM and WN are supported by Innovate UK (10058536). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There is a newer version of this article available. of this article available. Many people living with serious, incurable illnesses will experience problems with pain, nausea, vomiting and other symptoms that affect their quality of life. Where these symptoms are associated with the treatment of life limiting conditions, it may affect how likely someone is to take those medications, or lead to further complications. Palliative and supportive care aims to relieve or reduce symptoms arising from serious illness or its treatment. Commonly, this involves the use of opioids and non-steroidal anti-inflammatory drugs for pain management, anti-emetics for nausea and vomiting and a myriad of other supportive care medications (SCM). Symptom control in this patient cohort can be challenging due to varying responses to medication, polypharmacy burden/known drug-drug interactions, and frailty or co-existing comorbidities. Up to a third of bereaved relatives report inadequate symptom control after a hospital death1. Complaints about the quality of pain management towards the end of life are common2. With an estimated 20 people a day dying in pain in hospitals across the UK3. Pharmacogenomics (PGx) is an area of expanding research, which could indicate whether an individual is likely to benefit from a SCM, based on their genetic profile. PGx can identify genetic variations that influence the metabolism of certain medications, leading to variations in effects between individuals. Most people carry at least one pharmacogenetic variant that could influence their response to a medicine4. Common variation in an individual’s genetic code can lead to functional variation in the expressed proteins, including enzymes and drug transporters5. This is particularly relevant in the cytochrome P450 family of genes, where variation can lead to the production of enzymes with differential activity profiles. For example, genetic variation in the CYP219 gene can impact the activity of the cytochrome P450-2C19 (CYP2C19) protein. This leads to a spectrum of potential phenotypes, ranging from poor metabolisers (PM), intermediate metabolisers (IM), normal metabolisers (NM), rapid metabolisers (RM) to ultra-rapid metabolisers (UM) of various medications. It is now possible to perform genetic testing to predict an individual’s functional phenotype for a given pharmacogene. This information can then be used to guide prescribing for a wide range of medications against published expert advice6. Single-gene tests are currently available in many health systems around the world to guide prescribing, including the NHS where all patients receiving fluoropyrimidine chemotherapy agents or mavacamten must have pharmacogenetic testing prior to prescription7. In recent years, many health systems have begun to explore the use of panel based genetic testing, which analyses variants across multiple genes at the same time. However, these are comparatively rarely used in the United Kingdom (UK) despite the potential economic impact8. Many of the medications used in palliative and supportive care may be susceptible to drug-gene interactions, which may determine how effective those medications are at achieving symptom control and a “good death”. This is particularly important in a palliative care context, where achieving adequate pain or symptom management in a timely manner is often the overriding therapeutic aim. The existing evidence base for PGx predominantly concerns the medicines prescribed in cardiology, stroke, psychiatry and oncology6. This evidence originates from trials conducted mostly outside of the UK, with different funding models and therefore health economic impact calculations that are less relevant to National Health Service (NHS) practice9,10. Our recent review into pharmacogenomics and symptom management in palliative care found that pharmacogenomic testing, to identify drug-gene interactions was feasible in palliative care setting (predominantly North America)11. Many drugs used commonly in palliative care were amenable to a pharmacogenomic approach, with data suggesting that PGx information might result in a change in prescribing advice in around a quarter of cases12. It would seem a logical extension from this point to suggest that PGx therefore could improve symptom control in supportive and palliative care, but to date no trials have been reported in the UK or Europe that could answer either the potential drug-gene interaction ratio in this patient population, nor the feasibility of doing PGx testing in a UK supportive/palliative care setting. Without this data, it is impossible to calculate the clinical utility of adopting such an approach. ‘Clinical utility’ often refers to the likelihood that a test will, by prompting an intervention, result in an improved health outcome. In this context, clinical utility might specifically refer to improved symptom management from prescribing changes informed by an identified drug-gene interaction. Addressing the paucity of evidence around real-world clinical utility is an essential step in policy and practice development13. The Pharmacogenomics to Improve Supportive Care Symptoms (PISCES) study aims to understand the acceptability and feasibility of recruiting NHS patients into a pharmacogenomics research study in a palliative and supportive care context, and also to provide preliminary data on drug-gene interaction prevalence (how often a potentially actionable genetic variation is found paired to an existing prescription of a medication in the same patient). We aim to use data to inform study design of future clinical trials that can definitively address the question of clinical utility in this population. This is a prospective, observational cross-sectional study of adult patients with serious and/or life limiting conditions, such as incurable cancer undergoing palliative or supportive care treatment. Ethical consent statement: All participants in this study will undergo written informed consent. Participants will receive the usual standard of care for their condition, and from enrolment will have all their medication use recorded for a 90-day period. They will have a single blood test that will be analysed for CYP2D6, CYP2C19 and CYP2C9 variants. This genetic analysis will take place after study data collection for medication use is complete. We will use this data to ascertain whether there were any clinically actionable drug gene interactions for a subset of medications used in supportive and palliative care treatment compared with their medication usage at enrolment (see Pharmacogenomic analysis section below for explanation of difference between “clinically relevant” and “clinically actionable” results). We will adhere to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational cohort studies - https://www.strobe-statement.org/ We have conducted Patient and Public Involvement (PPI) workshops to seek feedback on conducting research in this area in this patient group. All PPI attendees had personal experience of palliative care delivered to someone in their family. They gave universal support for the idea of doing research generally in palliative care setting and they specifically felt there was value for learning more about the utility of pharmacogenomic testing in general. Primary aim (or Research Question) How could the introduction of multi-gene pharmacogenetic test for patients receiving palliative and supportive care could impact routine prescribing practice in an acute NHS hospital setting? Primary and secondary outcome measures are illustrated in Table 1, and the objectives behind these described below in more detail. Primary Objective: To understand the clinical utility of multi-gene pharmacogenetic testing in patients receiving palliative and supportive care across palliative care settings (inpatient hospital, outpatient), specifically by calculating a drug-gene interaction (DGI) ratio, based on extant prescriptions at time of recruitment paired with an individual’s “clinically actionable” pharmacogenetic results. We will also report the proportion of subjects that have at least one clinically actionable DGI out of all subjects in the study. Secondary Objective: To report on the nature and variation of prescribing patterns between patients with and without the presence of clinically actionable drug-gene interactions To report on the feasibility of incorporating PGx testing in a supportive and palliative care setting (in an acute hospital setting) via achievement of recruitment targets Lacks capacity to decide on research participation/ is unable to consent to research participation due to impaired mental capacity Prognosis likely less than one week (as judged by named clinician in charge of care) Enrolment in clinical trial of a supportive care / symptom management medication (those on clinical trials for disease modifying cancer therapy can be included). Under 18 years old Patient recruitment is expected to take place between May 2025 and November 2025 at the Norfolk and Norwich University Hospitals NHS Trust (NNUH). Individuals referred to the in-patient palliative care service at NNUH or attending out-patients with oncology or palliative care will be informed about the study by their clinician, or a supporting health-care professional, and offered a short form patient information sheet. Patients who are interested in joining the study will be asked for permission to share their contact details with the study team. This will be done verbally, with site staff sending an electronic or paper notification of consent to contact to the research team. On receipt of referral, a trained member of research team member will visit in person (if still an in-patient) or telephone potential participants to explain the study. Following this, the team will send a long form patient information sheet to potential participants. If the participant would like to join the study, the research team will arrange a study visit (either as an in-patient, or to coincide with next out-patient attendance) for formal consenting and obtaining a 5ml blood sample. We will record the numbers of potential participants who decline participation, and any reasons given, where possible. No financial or non-financial incentives are offered to participants. All participants will undergo testing of a panel of genetic variants linked with medications commonly used in symptom control for which there is internationally recognised guidance on PGx testing (see Table 2)14. This will involve collecting a 5mL blood sample from individuals. All participants will be consented to examination of their records within local hospitals and/or primary care to extract study relevant data on prescribing. The start of the 90-day follow-up will be from the date of the blood sample. Standard demographic information including ethnicity will be collected at baseline. Pharmacogenomics assay DNA will be extracted from the participant blood samples in an ISO15189 accredited laboratory (NHSE NW Genomics Lab Hub) at Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust. We will use the Agena VeriDose® Core Panel v2.0 panel, plus digital PCR assay for CYP2D6 genotyping. Both assays have been used in the NHS PROGRESS study (ISRCTN15390784). We may set up an alternative assay(s) (dependent upon analytical validity, cost and ease of use if this becomes available), which covers the same genetic variants. No other genetic tests will be performed without consent. Unused DNA samples will be returned to NNUH on completion of the study. We will analyse the results of a number of variants in CYP2C9, CYP2C19 and CYP2D6, as variants in these three genes are connected to the predicted response to drugs used in palliative symptom control and have specific internationally agreed CPIC guidance14. Therefore, defined actions can be recommended dependent upon the results namely: CYP2C19 - proton pump inhibitors, CYP2C9 – NSAIDs; and CYP2D6 – ondansetron, tropisetron and opioids. The potential impact of pharmacogenetic testing, had the data been available at the point of prescribing, will be categorized as either ‘no impact’, ‘clinically relevant’ or ‘clinically actionable’ based on CPIC guidance and previously published definitions15. A ‘clinically actionable’ interaction is defined as one where the recommended action within current CPIC guidance is to either alter the chosen medicine or alter the dose of the same medicine. A ‘clinically relevant’ interaction is where the gene–drug interaction conferred increased risk of an adverse drug reaction (ADR) or reduced effectiveness, though the recommended action was to initiate therapy at a standard dose. Our primary outcome will be calculated based on clinically actionable results only. Baseline characteristics of each participant will be aggregated and summarised, including age, sex, allergy status, ethnicity, diagnosis, and medications prescribed. For categorical variables, the number and percentage will be presented. For continuous variables, the mean (and standard deviation) or median (and interquartile range) will be presented depending on the distribution. We will report data on our primary and secondary outcome measures as detailed above, and we will also report data on: 1. Number of participants with at least one clinically actionable genetic variant related to a medication they were prescribed, and proportions of participants with at least one clinically actionable or clinically relevant result vs those with zero. 2. Estimated number of patients where the genetic variant result could influence future prescribing Further details on feasibility and acceptability of any future interventional trial will be evaluated by: Number of potentially eligible participants who meet the inclusion criteria Number of participants subsequently recruited into the study % of patients where full prescribing data can be accessed by digital only methods to understanding prescribing patterns over acute, primary and hospice care. % of patients with incomplete pharmacogenetic data (where some genetic variants have failed) due to low DNA yield from blood sampling or other technical factors. In designing the study, we have considered the potential disadvantages for participation for people living with incurable illness, and whether a further observational study into PGx is justified given the existing international evidence base. At present, within the UK there is clinical equipoise as to whether PGx testing is likely to change clinical outcomes. Furthermore, there is limited European data as to the acceptability of testing in this population. This study gives up the opportunity to learn about the acceptability of PGx testing for those approaching the end of life, and we will report on screening/recruitment rates to understand how acceptable our approach is. As this is an observational study, we will make it clear that there is no plan to feedback results to individual participants, and that all participants will receive standard care. We will however offer the opportunity to receive a lay summary of the overall results and impact of the study. This was granted by London-Surrey Research Ethics Committee, 10th March 2025, IRAS project ID: 354053. All participants in this study will undergo written informed consent.

of the study are common to many single site, observational studies of this nature. Findings arising from this study may not be generalisable across all palliative care populations. The study site is an area of low ethnic diversity and there we anticipate that our study sample may not be fully representative of the population. We will try and purposively sample people from non-white backgrounds were possible to redress this. A further limitation is absence of retrospective data collection on medicines use. Whilst the results will capture both current and future SCM, it will not consider medications that have previously been tried and subsequently stopped either due to ineffectiveness or side effects. This may mean that our results are not fully reflective of the potential clinical utility of PGx testing throughout the illness journey. Ethical approval has been granted by London-Surrey Research Ethics Committee, 10th March 2025, IRAS project ID: 354053. CQUIN - Commissioning for Quality and Innovation PGx - pharmacogenomics SCM - supportive care medications PM – poor metaboliser IM – intermediate metaboliser NM – normal metaboliser UM – ultra metaboliser NHS - National Health Service UK – United Kingdom PISCES - Pharmacogenomics to Improve Supportive Care Symptoms PPI – Patient and Public Involvement NNUH - Norfolk and Norwich University Hospitals NHS Trust Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this protocol, i.e. “No data are associated with this article. We wish to thank Dr Sion Scott and Debbie Critoph who kindly provided independent, external peer review comments on the original protocol. We also wish to thank members of our patient and public experience group who gave their time to help us develop the study. Faculty Opinions recommendedReferences - 1. National audit of care at the end of life, 2024. Accessed 17 Sept 2025. Reference Source - 2. Parliamentary and health service ombudsman annual report 2015. Accessed 17 Sept 2025. Reference Source - 3. Marie curie better end of life report. 2024; Accessed Sept 2025. Reference Source - 4. McInnes G, Lavertu A, Sangkuhl K, et al.: Pharmacogenetics at scale: an analysis of the UK Biobank. Clin Pharmacol Ther. 2021; 109(6): 1528–37. PubMed Abstract | Publisher Full Text | Free Full Text - 5. Roden DM, McLeod HL, Relling MV, et al.: Pharmacogenomics. Lancet. 2019; 394(10197): 521–32. PubMed Abstract | Publisher Full Text | Free Full Text - 6. Crews KR, Monte AA, Huddart R, et al.: Clinical pharmacogenetics implementation consortium guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther. 2021; 110(4): 888–96. PubMed Abstract | Publisher Full Text | Free Full Text - 7. Shaunak N, Keen J, Kim A, et al.: Implementation of mass pharmacogenetic testing: dihydropyrimidine dehydrogenase testing prior to fluoropyrimidine treatment for patients. Br J Clin Pharmacol. 2025; 91(9): 2534–2542. PubMed Abstract | Publisher Full Text - 8. Youssef E, Kirkdale CL, Wright DJ, et al.: Estimating the potential impact of implementing pre-emptive pharmacogenetic testing in primary care across the UK. Br J Clin Pharmacol. 2021; 87(7): 2907–25. PubMed Abstract | Publisher Full Text - 9. Penno E, Gauld R, Audas R: How are population-based funding formulae for healthcare composed? A comparative analysis of seven models. BMC Health Serv Res. 2013; 13: 470. PubMed Abstract | Publisher Full Text | Free Full Text - 10. Papanicolas I, Woskie LR, Jha AK: Health care spending in the United States and other high-income countries. JAMA. 2018; 319(10): 1024–39. PubMed Abstract | Publisher Full Text - 11. Barry C, Patel M: Pharmacogenomics and symptom management in palliative and supportive care: a scoping review. BMJ Support Palliat Care. 2025; 15(2): 158–67. PubMed Abstract | Publisher Full Text - 12. Patel JN, Boselli D, Jandrisevits EJ, et al.: Potentially actionable pharmacogenetic variants and symptom control medications in oncology. Support Care Cancer. 2021; 29(10): 5927–34. PubMed Abstract | Publisher Full Text - 13. Roberts MC, Kennedy AE, Chambers DA, et al.: The current state of implementation science in genomic medicine: opportunities for improvement. Genet Med. 2017; 19(8): 858–63. PubMed Abstract | Publisher Full Text | Free Full Text - 14. Clinical pharmacogenetics implementation consortium guidelines. Accessed 17 September 2025. Reference Source - 15. McDermott JH, Burke K, Fullerton N, et al.: Pre-emptive pharmacogenetic testing in the acute hospital setting: a cross-sectional study. QJM. 2025; 118(3): 154–160. PubMed Abstract | Publisher Full Text | Free Full Text - 16. Patel M, McDermott JH, Newman WG, et al.: Pharmacogenomics to improve supportive care symptoms. A prospective observational study protocol. Research Square. PREPRINT (Version 1). 2025. Publisher Full Text Author details Author details 1 Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England, UK 2 University of East Anglia Norwich Medical School, Norwich, England, UK 3 Manchester University NHS Foundation Trust, Manchester Centre for Genomic Medicine, Manchester, England, UK 4 Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, England, UK 2 University of East Anglia Norwich Medical School, Norwich, England, UK 3 Manchester University NHS Foundation Trust, Manchester Centre for Genomic Medicine, Manchester, England, UK 4 Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, England, UK Martyn Patel Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing John McDermott Roles: Methodology, Project Administration, Resources, Visualization, Writing – Review & Editing Roles: Methodology, Project Administration, Resources, Visualization, Writing – Review & Editing William Newman Roles: Methodology, Supervision, Writing – Review & Editing Roles: Methodology, Supervision, Writing – Review & Editing Caroline Barry Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This project is funded by the National Institute for Health Research (NIHR) under its Biomedical Research Centre (BRC) Programme (Grant Reference Number NIHR 203956)]. This project is also funded by the National Institute for Health Research (NIHR) under its Research Career Funding - Doctoral Fellowship (DRF) Programme (Grant Reference Number NIHR 301748). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was funded by the NHS England Genomics Programme through the Pharmacogenetics and Medicines Optimisation Network of Excellence. Additionally, JHM and WN are supported by Innovate UK (10058536). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was funded by the NHS England Genomics Programme through the Pharmacogenetics and Medicines Optimisation Network of Excellence. Additionally, JHM and WN are supported by Innovate UK (10058536). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) Copyright © 2025 Patel M et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Patel M, McDermott J, Newman W and Barry C. Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.14182.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 22 Dec 2025 Views 0 How to cite this report: Somogyi A. Reviewer Report For: Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.15438.r39369) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-39369 https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-39369 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 12 Feb 2026 Approved with Reservations VIEWS 0 A reasonably well-written protocol designed to pilot a potential future study in a cohort of patients in palliative & supporting care, for whom pharmacogenomic testing and outcomes (acceptability, feasibility and implementation) has not been evaluated. Apart from the ... Continue reading 2. Robinson K, Eum S, Desta Z, Tyndale R, et al.: Clinical Pharmacogenetics Implementation Consortium Guideline forCYP2B6 Genotype and Methadone Therapy. Clinical Pharmacology & Therapeutics. 2024; 116 (4): 932-938 Publisher Full Text I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close Apart from the ... Continue reading A reasonably well-written protocol designed to pilot a potential future study in a cohort of patients in palliative & supporting care, for whom pharmacogenomic testing and outcomes (acceptability, feasibility and implementation) has not been evaluated. Apart from the drug-drug interactions concern that can lead to false phenotyping and should be considered, there are a few other issues that could be addressed. That pain and nausea/vomiting are the only symptoms to be addressed from a medications perspective, but fatigue (antidepressants/diazepam) and constipation (often from opioids) could be considered as they are common. Prescribing patterns are from enrolment to 90 days. In such patient cohorts, SCM doses can be changed and drugs switched within the 90 days and those data and reasons for such changes appear not being documented. CPIC guidelines will be used for evaluation to address the aims as per Table 2; however, the evidence for CYP2D6 phenotype based on genotype altering oxycodone dosage per se shows lack of evidence and CYP2D6 only relates to codeine and tramadol which are infrequently used in palliative care. Also, methadone is predominantly metabolised by CYP2B6 (especially the S-enantiomer) and CPIC guidelines do not support a change in dosage. Given that medication side-effects are an important criterion for pharmacogenomic testing and that the planned patient population will be on multiple medications that may have a pharmacogenomic footprint, medication side effects should be considered. Apart from the drug-drug interactions concern that can lead to false phenotyping and should be considered, there are a few other issues that could be addressed. That pain and nausea/vomiting are the only symptoms to be addressed from a medications perspective, but fatigue (antidepressants/diazepam) and constipation (often from opioids) could be considered as they are common. Prescribing patterns are from enrolment to 90 days. In such patient cohorts, SCM doses can be changed and drugs switched within the 90 days and those data and reasons for such changes appear not being documented. CPIC guidelines will be used for evaluation to address the aims as per Table 2; however, the evidence for CYP2D6 phenotype based on genotype altering oxycodone dosage per se shows lack of evidence and CYP2D6 only relates to codeine and tramadol which are infrequently used in palliative care. Also, methadone is predominantly metabolised by CYP2B6 (especially the S-enantiomer) and CPIC guidelines do not support a change in dosage. Given that medication side-effects are an important criterion for pharmacogenomic testing and that the planned patient population will be on multiple medications that may have a pharmacogenomic footprint, medication side effects should be considered. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Partly - Are sufficient details of the methods provided to allow replication by others? Partly - Are the datasets clearly presented in a useable and accessible format? Yes

1. Crews K, Monte A, Huddart R, Caudle K, et al.: Clinical Pharmacogenetics Implementation Consortium Guideline forCYP2D6 ,OPRM1 , andCOMT Genotypes and Select Opioid Therapy. Clinical Pharmacology & Therapeutics. 2021; 110 (4): 888-896 Publisher Full Text2. Robinson K, Eum S, Desta Z, Tyndale R, et al.: Clinical Pharmacogenetics Implementation Consortium Guideline forCYP2B6 Genotype and Methadone Therapy. Clinical Pharmacology & Therapeutics. 2024; 116 (4): 932-938 Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Pharmacogenomics in palliative medicine CITE HOW TO CITE THIS REPORT Somogyi A. Reviewer Report For: Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.15438.r39369) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-39369 https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-39369 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 10 Apr 2026Martyn Patel, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK10 Apr 2026Author ResponseREVIEWER 2 - Thank you for acknowledging the importance of this topic - We have expanded on the nature of side effects from SCM in the introduction - With - Thank you for acknowledging the importance of this topic - We have expanded on the nature of side effects from SCM in the introduction - With regards to patterns in medication changes over the 90 day period, we are committed to checking for the reasons for switching of medications, and will document this where that information is available. One of our main feasibility questions is whether we can gather sufficient information about medicines changes from e-records alone, to avoid having to ask patients to fill in medication diary cards, making a future trial less burdensome. If this is not possible, that will itself be useful information. We have now amended the Limitations section to acknowledge the potential weakness of our current approach to side effect data collection in the limitations section. - We are aware that the evidence base for pharmacogenomic prescribing guidance and opiates has weakened over time. This is why we chose a “panel” test approach to cover medication across different classes. We feel it will still be of interest to collect information on strong opiate related genetic variation, even if it currently does not impact prescribing as per CPIC guidelines. Our patient and public involvement groups were keen on multiple symptoms being considered within this study – we will make this clearer in the revised text. - In our UK based experience patients are still sometimes prescribed “weak opiates” such as codeine and tramadol, but we acknowledge there is variance in this internationally. We will report on the nature of opiate prescribing in this cohort, which again will influence future trial design. - We have removed methadone from our table of medications, thank you for pointing this out, and will consider CYP2B6 testing in future trials. - With regards to capturing medication side effects. As mentioned, we are aiming for a light touch patient data collection, to encourage/enable participation. We have found that when prescriptions are changed, the specialist team letter to the primary care team does often mention side effects that led to the change, and we are noting these. Again, we will report if this is insufficient for our needs. REVIEWER 2Competing Interests: No competing interests were disclosed. Close- Thank you for acknowledging the importance of this topic - We have expanded on the nature of side effects from SCM in the introduction - With regards to patterns in medication changes over the 90 day period, we are committed to checking for the reasons for switching of medications, and will document this where that information is available. One of our main feasibility questions is whether we can gather sufficient information about medicines changes from e-records alone, to avoid having to ask patients to fill in medication diary cards, making a future trial less burdensome. If this is not possible, that will itself be useful information. We have now amended the Limitations section to acknowledge the potential weakness of our current approach to side effect data collection in the limitations section. - We are aware that the evidence base for pharmacogenomic prescribing guidance and opiates has weakened over time. This is why we chose a “panel” test approach to cover medication across different classes. We feel it will still be of interest to collect information on strong opiate related genetic variation, even if it currently does not impact prescribing as per CPIC guidelines. Our patient and public involvement groups were keen on multiple symptoms being considered within this study – we will make this clearer in the revised text. - In our UK based experience patients are still sometimes prescribed “weak opiates” such as codeine and tramadol, but we acknowledge there is variance in this internationally. We will report on the nature of opiate prescribing in this cohort, which again will influence future trial design. - We have removed methadone from our table of medications, thank you for pointing this out, and will consider CYP2B6 testing in future trials. - With regards to capturing medication side effects. As mentioned, we are aiming for a light touch patient data collection, to encourage/enable participation. We have found that when prescriptions are changed, the specialist team letter to the primary care team does often mention side effects that led to the change, and we are noting these. Again, we will report if this is insufficient for our needs. COMMENTS ON THIS REPORT - Author Response 10 Apr 2026Martyn Patel, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK10 Apr 2026Author ResponseREVIEWER 2 - Thank you for acknowledging the importance of this topic - We have expanded on the nature of side effects from SCM in the introduction - With - Thank you for acknowledging the importance of this topic - We have expanded on the nature of side effects from SCM in the introduction - With regards to patterns in medication changes over the 90 day period, we are committed to checking for the reasons for switching of medications, and will document this where that information is available. One of our main feasibility questions is whether we can gather sufficient information about medicines changes from e-records alone, to avoid having to ask patients to fill in medication diary cards, making a future trial less burdensome. If this is not possible, that will itself be useful information. We have now amended the Limitations section to acknowledge the potential weakness of our current approach to side effect data collection in the limitations section. - We are aware that the evidence base for pharmacogenomic prescribing guidance and opiates has weakened over time. This is why we chose a “panel” test approach to cover medication across different classes. We feel it will still be of interest to collect information on strong opiate related genetic variation, even if it currently does not impact prescribing as per CPIC guidelines. Our patient and public involvement groups were keen on multiple symptoms being considered within this study – we will make this clearer in the revised text. - In our UK based experience patients are still sometimes prescribed “weak opiates” such as codeine and tramadol, but we acknowledge there is variance in this internationally. We will report on the nature of opiate prescribing in this cohort, which again will influence future trial design. - We have removed methadone from our table of medications, thank you for pointing this out, and will consider CYP2B6 testing in future trials. - With regards to capturing medication side effects. As mentioned, we are aiming for a light touch patient data collection, to encourage/enable participation. We have found that when prescriptions are changed, the specialist team letter to the primary care team does often mention side effects that led to the change, and we are noting these. Again, we will report if this is insufficient for our needs. REVIEWER 2Competing Interests: No competing interests were disclosed. Close- Thank you for acknowledging the importance of this topic - We have expanded on the nature of side effects from SCM in the introduction - With regards to patterns in medication changes over the 90 day period, we are committed to checking for the reasons for switching of medications, and will document this where that information is available. One of our main feasibility questions is whether we can gather sufficient information about medicines changes from e-records alone, to avoid having to ask patients to fill in medication diary cards, making a future trial less burdensome. If this is not possible, that will itself be useful information. We have now amended the Limitations section to acknowledge the potential weakness of our current approach to side effect data collection in the limitations section. - We are aware that the evidence base for pharmacogenomic prescribing guidance and opiates has weakened over time. This is why we chose a “panel” test approach to cover medication across different classes. We feel it will still be of interest to collect information on strong opiate related genetic variation, even if it currently does not impact prescribing as per CPIC guidelines. Our patient and public involvement groups were keen on multiple symptoms being considered within this study – we will make this clearer in the revised text. - In our UK based experience patients are still sometimes prescribed “weak opiates” such as codeine and tramadol, but we acknowledge there is variance in this internationally. We will report on the nature of opiate prescribing in this cohort, which again will influence future trial design. - We have removed methadone from our table of medications, thank you for pointing this out, and will consider CYP2B6 testing in future trials. - With regards to capturing medication side effects. As mentioned, we are aiming for a light touch patient data collection, to encourage/enable participation. We have found that when prescriptions are changed, the specialist team letter to the primary care team does often mention side effects that led to the change, and we are noting these. Again, we will report if this is insufficient for our needs. Views 0 How to cite this report: Pratt V. Reviewer Report For: Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.15438.r38978) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-38978 https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-38978 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 07 Jan 2026 Approved with Reservations VIEWS 0 Overall, this is a well-written manuscript. I have one major concern related to the study design. The authors plan to evaluate drug-gene interactions, but do not plan to study drug-drug-gene interactions. Patients receiving palliative or support care are often on ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close Overall, this is a well-written manuscript. I have one major concern related to the study design. The authors plan to evaluate drug-gene interactions, but do not plan to study drug-drug-gene interactions. Patients receiving palliative or support care are often on many medications which can impact the predicted phenotype based on the genotype alone. There are a few minor points. The authors use the word "carry". While derived from genetics where a carrier of a pathogenic variant typically for an autosomal recessive disorder does not clinical symptoms. Though this term, carrier, is pervasive in pharmacogenetics, it would be better to use the term have/having as individuals with a pharmacogenetic variant often will have a phenotype. PGx testing helps predict an individual's phenotype. Drug-drug-gene interactions can alter a predicted phenotype. Please check spelling of neurone Please check if 1st person is permittable Please use HGVS nomenclature. All genes should be italicized. The study refers to a past date. Please confirm and update tense, if applicable. There are a few minor points. The authors use the word "carry". While derived from genetics where a carrier of a pathogenic variant typically for an autosomal recessive disorder does not clinical symptoms. Though this term, carrier, is pervasive in pharmacogenetics, it would be better to use the term have/having as individuals with a pharmacogenetic variant often will have a phenotype. PGx testing helps predict an individual's phenotype. Drug-drug-gene interactions can alter a predicted phenotype. Please check spelling of neurone Please check if 1st person is permittable Please use HGVS nomenclature. All genes should be italicized. The study refers to a past date. Please confirm and update tense, if applicable. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Partly - Are sufficient details of the methods provided to allow replication by others? Yes - Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: Employee of Agena Bioscience Reviewer Expertise: Pan-ethnic pharmacogenetic testing. PGx implementation. CITE HOW TO CITE THIS REPORT Pratt V. Reviewer Report For: Pharmacogenomics to Improve Supportive Care Symptoms. A Prospective Observational Study Protocol [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2025, 5:125 (https://doi.org/10.3310/nihropenres.15438.r38978) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-38978 https://openresearch.nihr.ac.uk/articles/5-125/v1#referee-response-38978 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 10 Apr 2026Martyn Patel, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK10 Apr 2026Author ResponseResponse to peer review reports REVIEWER 1- We have added to our analysis plan to state we will also seek to identify the prevalence of potential drug-drug-gene interactions REVIEWER 1- We have added to our analysis plan to state we will also seek to identify the prevalence of potential drug-drug-gene interactions in this cohort. - We have changed “carry” to “have” as suggested. - We have added a sentence to reflect that drug-drug-gene interactions can potentially impact on phenotype. - It can be either neuron or neurone, with the latter most used in the UK, see this article – - Have italicised all genes in the text. - The dates for study commencement are correct, and it is conventionally permissible to publish the protocol after commencement, as long as it is before study activities are complete. This is due to the inherent time lag from first attempt to publish this protocol, to success. Response to peer review reportsCompeting Interests: No competing interests were disclosed. Close REVIEWER 1- We have added to our analysis plan to state we will also seek to identify the prevalence of potential drug-drug-gene interactions in this cohort. - We have changed “carry” to “have” as suggested. - We have added a sentence to reflect that drug-drug-gene interactions can potentially impact on phenotype. - It can be either neuron or neurone, with the latter most used in the UK, see this article – - Have italicised all genes in the text. - The dates for study commencement are correct, and it is conventionally permissible to publish the protocol after commencement, as long as it is before study activities are complete. This is due to the inherent time lag from first attempt to publish this protocol, to success. COMMENTS ON THIS REPORT - Author Response 10 Apr 2026Martyn Patel, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK10 Apr 2026Author ResponseResponse to peer review reports REVIEWER 1- We have added to our analysis plan to state we will also seek to identify the prevalence of potential drug-drug-gene interactions REVIEWER 1- We have added to our analysis plan to state we will also seek to identify the prevalence of potential drug-drug-gene interactions in this cohort. - We have changed “carry” to “have” as suggested. - We have added a sentence to reflect that drug-drug-gene interactions can potentially impact on phenotype. - It can be either neuron or neurone, with the latter most used in the UK, see this article – - Have italicised all genes in the text. - The dates for study commencement are correct, and it is conventionally permissible to publish the protocol after commencement, as long as it is before study activities are complete. This is due to the inherent time lag from first attempt to publish this protocol, to success. Response to peer review reportsCompeting Interests: No competing interests were disclosed. Close REVIEWER 1- We have added to our analysis plan to state we will also seek to identify the prevalence of potential drug-drug-gene interactions in this cohort. - We have changed “carry” to “have” as suggested. - We have added a sentence to reflect that drug-drug-gene interactions can potentially impact on phenotype. - It can be either neuron or neurone, with the latter most used in the UK, see this article – - Have italicised all genes in the text. - The dates for study commencement are correct, and it is conventionally permissible to publish the protocol after commencement, as long as it is before study activities are complete. This is due to the inherent time lag from first attempt to publish this protocol, to success. Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | || |---|---|---| | 1 | 2 | | | Version 2 (revision) 10 Apr 26 | read | read | | Version 1 22 Dec 25 | read | read | Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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