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Abstract
Introduction DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.
Methods and analysis Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.
Ethics and dissemination The ethics approval of the trial has been obtained from the Royal Children’s Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.
Trial registration number NCT05667766.
- Implementation Science
- Pharmacists
- Paediatric oncology
- Polypharmacy
- Pharmacology
- GENETICS
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Study design using a gold-standard randomised controlled trial.
Primary and secondary endpoints address current critical gaps in paediatric pharmacogenomic research literature.
Targeted paediatric cohort potentially not generalisable to all paediatric patients.
Not double-blinded due to the nature of the intervention and need to have pharmacogenomics results available for study reporting and clinician interpretation.
Introduction
Background and rationale
Genetic-informed prescribing, or indeed pharmacogenomic medicine, is an important arm of precision medicine that still requires implementation internationally.1 Germline testing of genes predisposing to drug toxicity or inefficacy can inform drug selection and drug dosing. Pharmacogenomic prescribing avoids the historical ‘trial and error’ approach. It is expectantly aimed at minimising adverse drug reactions (ADRs) and potentially results in health economic savings through a reduction in readmissions and admissions resulting from ADRs.
Since the mid-2000s the Dutch Pharmacogenetics Working Group2 and Clinical Pharmacogenetics Consortium (CPIC)3 have worked tirelessly to develop the evidence base for gene–drug interactions with available clinical practice guidelines providing therapeutic recommendations for high-risk diplotypes. Recent publications suggest that when these high-risk variants are screened for, approximately 97%4 of patients have at least 1 high-risk variant identified that would necessitate pharmacotherapy adjustment.
It is important to note that pharmacogenetic test results are relevant across an entire lifetime. Patients most likely to benefit from these results are those with comorbidities or receiving polypharmacy. Children, who have a cancer diagnosis or are undergoing haematopoietic stem cell transplantation (HSCT), are one such high-risk cohort that would benefit from pharmacogenomic informed prescribing. Systematic reviews have shown the broad reach of pharmacogenomic results in paediatric oncology and interest in identifying high-risk patients.5 Knowing which patients are at risk of ADRs (both toxicity and inefficacy) by virtue of their genotype is a necessary step forward in realising the potential of personalised medicine in paediatrics.6
Despite the establishment of international screening guidelines, the current standard of care (SOC) approach for paediatric patients with an oncology diagnosis in Australia involves pharmacogenomic testing for only two gene–drug pairs (TPMT and NUDT15) for patients with acute lymphoblastic leukaemia (ALL). Improving the clinical utility of pharmacogenomics (PGx) may reside in the ability to broader screen for pharmacogenomic markers which extend beyond the current limitations of specific gene–drug pairs.2 There are, however, many more opportunities to use pharmacogenomic informed prescribing across cancer therapeutics and supportive care as patients are often prescribed antibiotics, analgesics, antiemetics, antifungals and pain medication. Furthermore, the electronic medical record provides an opportunity to provide clinicians with clinical decision support tools and alert prescribers to a potential gene–drug interaction.
One international barrier to the widespread uptake of pharmacogenomic testing is the lack of evidence available to support its approach.7 While some institutes have initiated pre-emptive testing in paediatric patients (ie, St Jude Children’s Research Hospital8), the approach is not widely adopted. The Pre-emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions [ PREPARE trial9 ]from the Dutch group is the only study to date (in an Adult population) that has proven pre-emptive prescribing reduces ADRs in a broad cohort.3 However, extrapolating this efficacy to paediatrics is marred by differences in comorbidities, medication prescriptions, ontogeny and disease spectrum.
Hence, there is an opportunity to answer a critical question that remains in paediatrics—to determine the utility and cost-efficacy of pre-emptive PGx testing. The Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL-PIC) Australian study will use a randomised controlled trial to determine whether pre-emptive pharmacogenomic testing in paediatric patients with a new cancer diagnosis or proceeding to HSCT reduces ADRs and is cost-effective.
Objectives
Hypothesis
Patients with an actionable PGx variant (aPGx), taking a medication metabolised via the gene, will have a reduction in ADRs when international dosing gene–drug recommendations are adhered to, with a subsequent cost saving to the healthcare system.
Primary objective
The primary objective is to determine whether implementing pharmacogenomic testing across a range of clinically relevant variants, to guide the dose and drug selection of 27 commonly prescribed drugs used in cancer treatment and supportive care, will result in an overall reduction in clinically relevant ADRs.
Secondary objective
To evaluate the economic, quality of life (QoL) and workforce impacts of pre-emptive pharmacogenomic testing.
Trial design
MARVEL-PIC was designed as a multicentre, randomised, controlled trial of pre-emptive pharmacogenomic testing. The MARVEL-PIC (V.7.1) protocol conforms with the Standard Protocol Item Recommendation for Interventional Trials 2013 guideline.10 This trial is registered on ClinicalTrials.gov (NCT 05667766) and sponsored by Murdoch Children’s Research Institute listed (19 December 2022).
The broad aim of this trial is to provide gold-standard evidence of the utility of gene-drug pre-emptive testing to guide drug dosing, drug selection and reduce ADRs in a paediatric oncology population.
Participants are randomised to receive SOC prescribing (SoC—control) versus extended pharmacogenomic testing/prescribing (intervention arm) for a period of 12 weeks.
The flow diagram for MARVEL-PIC is shown in figure 1.
MARVEL-PIC study randomisation and overview patients will be randomised on enrolment to either (1) Standard of care or (2) extended pharmacogenomics (intervention arm). *Denotes tests that are already performed as standard of care for patients with acute lymphoblastic leukaemia. ADR, adverse drug reactions; CTCAE, Common Terminology Criteria for Adverse Events; MARVEL-PIC, Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children; MBS, Medical Benefits Schedule; PBS, Pharmaceutical Benefits Schedule; PGx, pharmacogenomics; QoL, quality of life.
Methods: participants, interventions, outcomes
Study setting
This study includes patients being treated at any of the participating tertiary oncology and HSCT units in Australia who have a new diagnosis of cancer (primary or relapsed) or are proceeding to HSCT and who are prescribed and receiving at least one of the 27 drugs included in the pre-emptive testing (table 1).
Gene–drug pairs and their associated diplotypes screened for in MARVEL-PIC
Eligibility criteria
Participants inclusion criteria
Age <18 years.
Starting cancer treatment (new cancer diagnosis or patient receiving HSCT or are a relapsed patient starting treatment after more than 6 months without oncological treatment).
Must receive a first prescription in routine care for one or more of the drugs for which the CPIC guideline is available.
The patient and/or legal guardian is able and willing to give consent for the patient to take part and be followed up for at least 12 weeks.
The patient amenable to venepuncture and blood draw (5 mL ideally, with an absolute minimum requirement of 2.5 mL).
The patient and/or legal guardian is able and willing to sign an informed consent form.
The patient and/or legal guardian can complete Ped-PRO-Common Terminology Criteria for Adverse Events (CTCAE) survey in one of the following languages (English, Italian or Chinese).
Study enrolment limit has not been reached.
Participants exclusion criteria
Age ≥18 years.
The patient has a life expectancy estimated to be less than 12 weeks by the treating clinical team.
Duration of the drug of inclusion total treatment length is planned to be less than 1 week.
The patient and/or legal guardian is unable to consent to the study.
The patient and/or legal guardian is unwilling to take part in the study.
The patient and/or legal guardian is unable to complete Ped-PRO-CTCAE survey in one of the following languages (English, Italian or Chinese).
The patient has existing impaired hepatic or renal function for which a lower dose or alternate drug selection is already part of current routine care.
The patient has a glomerular filtration rate of less than 15 mL/min per 1.73 m2.
The patient has advanced liver failure.
Interventions
Patients are randomised to (1) SoC or (2) Extended pharmacogenomic testing (intervention).
SOC: control arm
Currently, SoC involves pharmacogenomic testing for two gene–drug pairs (TPMT and NUDT15). This practice is indicated for ALL patients only. Patients who do not have ALL will not receive any routine pharmacogenetic testing.
Our team will perform whole genome sequencing on patients in the SoC arm to inform the study endpoint however, only results for TPMT and NUDT15 will be released to the patient as a clinical report during the first 12 weeks of the study. At week 13, the extended pharmacogenomic testing for the SoC arm will be released as a clinical report within the electronic medical record.
Extended pharmacogenomic testing: intervention arm
In addition to results for TPMT and NUDT15, patients on the intervention arm will be screened for gene–drug pairs across multiple diplotypes (table 1) with reporting of a metaboliser state for each gene. Metaboliser states will be described as either poor, intermediate, normal or ultra-metabolisers.
Outcomes
Primary outcome
The primary outcome is a reduction in ADRs among patients with aPGx, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities.
Secondary outcomes
Occurrence of at least one ADR which contributes to the primary endpoint.
Occurrence of at least one causal (definite, probable or possible), clinically relevant (classified as NCI-CTCAE grade 2, 3, 4 or 5), drug-genotype-specific ADR, attributable to an actionable drug, within 12 weeks of follow-up.
The number of self-reported ADRs per patient (average) linked to a cancer therapy.
The number of serious self-reported ADRs as measured by survey (independent of severity or drug–gene association) caused by cancer therapeutic.
The number of dose adjustments made to drug-gene-associated therapy during the study period (12 months).
Incidence of drug cessation due to ADR during study period (12 months).
Therapeutic drug monitoring (routine drug levels) performed during study period (12 months).
Physician and pharmacist adherence to pharmacogenomic report and international guidelines (12 months).
Healthcare expenditure related to adverse events (AEs).
QoL outcomes using child health survey (Child Health Utility 9D, CHU9D).
Methodology for primary outcome
To determine the primary outcome, an ADR must be determined. This is determined first by administering patient-reported surveys (National Cancer Institute—PED-PRO-CTCAE) at weeks 1, 6 and 12. Following each survey, within a 4-day period, an academic pharmacist carries out a semistructured interview for severity and causality associated with each ADR which is self-reported (figure 2).
MARVEL-PIC trial timeline. The MARVEL-PIC study has two study arms: (1) Standard of care (SOC) and (2) extended pharmacogenomics (intervention arm). Pharmacogenomic (PGx) screening will be performed on all patients, however, only the intervention arm will receive the extended panel of results. *At present, SOC involves pharmacogenomic testing for two gene–drug pairs (TPMT and NUD15). Ped-PRO CTCAE surveys and academic pharmacist semistructured interviews will occur at three time points over the 12-week ADR assessment period (red). Quality of life surveys will occur at 3 time points over 12 months (yellow). At week 13, the extended panel of results for the SoC arm will be released. ADR assessments will be stored in the REDCap database and downloaded for analysis. ADR: adverse drug reaction; CHU9D, Child Health Utility 9D; CTCAE, Common Terminology Criteria for Adverse Events.
The semistructured interviews include:
CTCAE grading of any self-reported Ped-PRO-CTCAE symptoms (above grade 0) (online supplemental appendix A).
Pharmacist lead CTCAE grading of any symptoms attributable to prescribed PGx actionable drugs (online supplemental appendix B).
Liverpool ADR causality assessment of reported ADRs (online supplemental appendix C).
Review of the participant’s electronic medical record and medication reconciliation (for trial endpoint data) (online supplemental appendix D).
Supplemental material
Methodology for secondary outcome
Patients will also consent to health economics analysis including collection of inpatient and outpatient cost data (Medical Benefits Schedule (MBS), Pharmaceutical Benefits Schedule (PBS) data from Services Australia and Population Health Research Network (PHRN). In addition, patients and/or legal guardians will complete the QoL surveys specific to children and young adults (CHU9D) at three time points over the 12-month participation period. Other secondary endpoints will be determined by mining the REDCap database and electronic medical record.
Participant timeline
Once the eligibility of the patients is confirmed, randomisation will be applied, and the intervention (whole genome sequencing (WGS) and pharmacogenomic testing) will be carried out. The assessment and visits for patients will be mandatory in the initial 12-week period. Each participant’s involvement in the trial will last 12 months, including the initial intervention period of 12 weeks, followed by a 1-year follow-up visit with completion of QoL survey (figure 3).
Schedule of assessments. *Conducted during semistructured interview performed by academic pharmacist. #Performed on both SoC and intervention arm on enrolment by the research assistant. **Optional consent. CTCAE, Common Terminology Criteria for Adverse Events; PGx, pharmacogenomics.
Sample size
The sample size calculation is based on showing a significant reduction in ADR events, among the subgroup of patients with at least one pharmacogenomic actionable variant. A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out. Sample size calculation is based on a required minimum of 100 patients per group with an aPGx, with 50% of patients expected to have aPGx thus requiring 200 patients per group (+20 allowing 10% drop-out). The target relative risk reduction corresponds to a clinically meaningful ~20% absolute risk reduction. An interim analysis will be performed once the study reaches 50% target enrolment to assess if the sample size calculation requires adjustment.
Recruitment
Achieving sample size
To reach the sample size, major paediatric tertiary hospitals have been chosen for recruitment throughout Australia. These include Perth Children’s Hospital, Women and Children’s Hospital South Australia, Sydney Children’s Network—Randwick and The Royal Children’s Hospital, Melbourne. Prior to opening at each site, estimated numbers of new cancer diagnoses in children were noted, allowing for the cumulative recruitment of n=440 patients over an estimated 3-year period.
Recruitment
Clinical trial assistants or academic pharmacists at each centre will screen eligible patients through the outpatient or inpatient department. The duration of the recruitment period is estimated to be a 48-month interval depending on each centre’s recruiting rate. No financial incentives will be provided to trial investigators or patients for enrolment in the recruitment period.
Allocation
Sequence generation and concealment
Participants will be randomly assigned to either the control or experimental group with a 1:1 allocation as per a computer-generated randomisation schedule. The randomisation is built into the REDCap database by the statistician and researchers remain blinded to this.
Implementation
Following consent, the research assistant[RA] or academic pharmacist enrolling the patient will enter details into the REDCap database. A randomisation status (intervention or SOC) is then generated and recorded in the REDCap database.
Blinding
The patients, pharmacists and physicians are unblinded to the study arm and to the pharmacogenomic results at week 1 for intervention arm and week 13 for SoC arm. Statisticians and health economic analysts are blinded. An aPGx is defined for patients with an abnormal metaboliser state who are on a medication where an international prescribing recommendations exists. As the primary outcome of this study is a reduction in ADRs in patients with an aPGx, this requires that treating physicians and pharmacists are unblinded for the purposes of prescribing medications.
Methods: data collection, management, analysis
Data collection primary outcome
Pharmacogenetic sequencing and diplotype interpretation
WGS will be performed on patients in both the SoC and intervention arm and provided by the Victorian Genetics Health Service. The sequencing will then be run through several software programmes to confirm the diplotype status including Stargazer,11 Aldy12 and Cyrius.13 Two tools for genotyping pharmacogenes will be used on each sequencing set to develop a consensus call. A bioinformatician is employed within the PGx Team for the purpose of this analysis. WGS was chosen as the methodology, rather than targeted sequencing or array, to facilitate discovery within the cohort for rare toxicities in later studies.
Once the genotype and diplotype consensus call is developed we will then use the CPIC proposed genotype to phenotype translation table to match detected genotypes with the predicted phenotype and associated activity score. The deduction of the phenotype is outlined within the CPIC guidelines and also called according to these guidelines using the outlined software.
The study team consisting of the principal investigator (PI), PhD student, academic pharmacist and bioinformatician will meet second weekly to discuss the phenotype and activity scores for the recently enrolled and sequenced patients. All participating institute team members (academic pharmacists and clinical research assistants) will be able to dial into this meeting remotely and finalise the results for their patient cohort using the MS Teams platform. After discussion and consensus, a clinical report will be generated for the purposes of the study.
The following data endpoints are annotated in the clinical report:
Screened variants and methodology.
Diplotype.
Phenotype status is reported as metaboliser state and activity score.
Therapeutic recommendations based on metaboliser state.
As described, the primary outcome is a reduction in ADRs among patients with actionable pharmacogenomic variants. An actionable pharmacogenomic variant is one where the following two conditions are met: (1) there is a therapeutic recommendation to decrease drug dosing, increasing drug dosing, increase therapeutic monitoring or cease the drug and (2) the patient is currently receiving a drug that is metabolised via this gene.
ADR assessments
To assess the primary outcome patients will be assessed for symptomatic toxicity and ADRs using the following approaches (figure 2):
Ped-PRO-CTCAE
Ped-PRO-CTCAE is an electronic patient-reported outcome measurement survey developed to evaluate symptomatic toxicity in consented MARVEL-PIC participants who are receiving cancer therapy. The PRO-CTCAE was developed by the National Cancer Institute in the USA (NCI). It includes 78 symptomatic toxicities drawn down from the CTCAE (the standard lexicon for AE reporting in clinical cancer studies). A paediatric model exists that permits self-reporting for children and adolescents aged 7–17 years (Ped-PRO-CTCAE) or alternatively parent/guardian reporting for patients unable to self-report. For the purposes of this study, we will use the Ped-PRO-CTCAE for parent(s)/guardian(s).
The Ped-PRO-CTCAE evaluates the symptom attributes of frequency, severity, interference, amount, presence and absence. Each symptomatic AE is assessed by 1–3 attributes that can be linked back to a CTCAE grade. The Ped-PRO-CTCAE has been trialled in the USA and has been linguistically validated in Italian and simplified Chinese.
The recall period for the Ped-PRO-CTCAE survey is the preceding 7 days prior to the academic pharmacist review. As such it is important to consider the commencement time point of the initial assessment survey carefully to allow subsequent time points to fall as conveniently as possible when implementing this approach allowing for accurate collection of data. As such, given the short recall period we have elected to generate REDCap surveys for enrolled participants to be delivery at the assessment time points. Assessments are performed at week 1, day 7, week 6, day 42, week 12 and day 84
Ped-PRO-CTCAE responses are scored from 0 to 3 (or 0/1 for absent/present). Currently, there are no standardised scoring rules for how to combine attributes into a single CTCAE score. For this reason, the academic pharmacist semistructured interviews will seek to ascribe CTCAE grades, alongside the Ped-PRO-CTCAE survey results.
Common Terminology Criteria for Adverse Events
The CTCAE is an internationally valid tool for assessing AEs of cancer therapeutics. As there are no standardised scoring rules for how to combine attributes into a single score, CTCAE grades for the corresponding time periods will be presented in conjunction with the Ped-PRO-CTCAE.
The academic pharmacist will conduct a semistructured interview focused on generating a CTCAE grade, for each of the areas from the Ped-PRO-CTCAE where a symptom was defined. These will occur within 4 days of the Ped-PRO-CTCAE being completed (see online supplemental appendix B for semistructured interview questions).
The CTCAE grade is scored from 0 to 5 (grade 0 baseline or no symptoms—grade 5 death related to AE) with unique clinical descriptions of severity for each AE based on these guidelines. The academic pharmacist will work through the answers to the Ped-PRO-CTCAE with the participant/parent/guardian and where positive scores were generated, ascribe a CTCAE grading.
Liverpool ADR CAT
The Liverpool ADR CAT (online supplemental appendix C) was developed to assess the possibility of avoiding ADRs and is suitable for use in the paediatric population. Possible avoidance is an important concept in the study of ADRs, particularly given that avoidable ADRs have a significant burden on the healthcare system and a cause of morbidity among outpatients.9 The avoidance categories defined within the tool include ‘unassessable’, ‘not avoidable’, ‘possibly avoidable’ and ‘definitely avoidable’. The Liverpool ADR CAT provides a mechanism for assessing causality of the ADR and was chosen for its excellent inter-rater reliability14 and ability to ascribe causality for the final endpoint (ADR).
The academic pharmacist will perform the Liverpool ADR CAT once CTCAE grades have been assigned for the symptomatic responses in the Ped-PRO-CTCAE, and Liverpool ADR CAT will be performed on any pharmacist CTCAE graded Ped-PRO-CTCAE, where the CTCAE grade is >2. All current medications (administered in last 7–14 days) will be noted, to assign causality.
Data collection secondary outcomes
Health economics outcomes
To achieve this secondary outcome, we will perform a health economics analysis incorporating QoL assessments.
Medicare Benefit Schedule and PBS data
Data will be collected on the costs of management comparing the SoC arm versus the intervention arm. Actual costs assigned to each inpatient or outpatient episode are separated into individual cost buckets will be collected. This information is readily accessible through Services Australia and the PHRN. Data will be requested from both Services Australia and the PHRN. Services Australia does not hold information about services that have been provided in public hospitals or services provided in outpatients or emergency departments of public hospitals. PHRN has access to all relevant data linkage units for all jurisdictions in Australia.
At the completion of cohort recruitment (12 months from the date of recruitment of the final patient), the PI and RA will contact Services Australia and PHRN advising that they are ready to request the consented data.
QoL assessments
To monitor changes in patient QoL, the CHU9D (University of Sheffield) will be used. The CHU9D consists of a descriptive system and a set of preference weights, giving utility values for each health state described by the descriptive system, allowing the calculation of quality-adjusted life-years for use in cost utility analysis. This tool is validated for use in children aged 7–18 years. Patient QoL will be assessed using the Assessment for QoL and the CHU9D. The CHU9D will be provided through REDCap at week −3 (baseline), week 12 and 12 months.
Retention
Retention in the study is aided by the RA conducting weekly quality assurance assessments on data collection. Patients are contacted to meet any outstanding endpoints. All study participants are provided with the ability to discuss their PGx report at the end of the intervention period (12 weeks) with a member of the study team. Weekly newsletters are provided via the hospital electronic mail system for awareness of the broader enrolling healthcare professional team.
Data management
Data forms and data entry
MARVEL-PIC results will be kept on a REDCap database. This is a secure database run by the Murdoch Children’s Research Institute. All paper files and consents will be secured in a locked filing cabinet within MCRI.
Data will be collected in an identifiable manner at each site. Patients will then be allocated a unique patient identifier prior to their deidentified data being added to the database by each participating site’s academic pharmacist or clinical research assistant. Each site will have quarantined data on REDCap allowing them to only access their site’s patient data.
Data collected through the study will be retrieved prior to entry into the REDCap database. Source documents (ie, pharmacist CTCAE grading proformas online supplemental appendix A,B) will also be stored on the REDCap database as PDF files, but the patient identifiable information will be removed and the unique patient identifier data applied to this data prior to inclusion, in addition to key endpoints being entered directly into data fields from these source documents on entry into the study.
Thus, although the information entered will be deidentified it will be reidentifiable to the researchers involved. Source documents will only consist of Pharmacist lead CTCAE Grading Ped-PRO-survey (online supplemental appendix A), CTCAE Grading PGX actionable drugs (online supplemental appendix B) or Liverpool ADR Causality Assessment Tool (online supplemental appendix C). Only the PI, RA(s) and PhD student will have access to reidentifiable information on participants in the registry for data entry purposes.
All registry data are protected within Murdoch Children’s Research Institute using the REDCap database by a triple encryption process between the remote user, the server and the REDCap database. No data can leave the database in identifiable format. All data extraction is deidentified for all users at all times, thus privacy and confidentiality will be maintained. The database itself is password protected and only researchers involved in the project will have access codes. These access codes will be changed at regular intervals to ensure integrity of the database.
To ensure patient data are protected when requesting MBS/PBS data from Services Australia and PHRN, data will be sent in a password-protected file or via another electronic platform (ie, secure portal). PHRN will store this data on a secure virtual machine with access restricted to the MARVEL-PIC health economist and relevant PHRN data team. Services Australia will retain Services Australia patient consent forms and data for the life of the study. The data will be deidentified once received, storing this information securely on Services Australia servers which are physically located within Australian borders. If patients withdraw from the study, a withdrawal of consent form will be sent to Services Australia and data will be securely destroyed.
Governance for data management and reporting
The PI is responsible for the design and conduct of the trial, preparation of protocol and revisions, preparation of case report forms within REDCap, organising steering committee (SC) meetings, managing the clinical trials office, publishing study reports and membership of the trial management committee (TMC). The SC agrees on the final protocol, which includes lead investigators from national sites with responsibilities of recruitment patients and liaising with the PI, reviewing study progress and if necessary, agreeing to changes of the protocol. TMC consists of the PI, academic pharmacists (CM, EW, RD, DK and BF), bioinformatician (AH) and research assistant (TS). The team contributes to organisation of SC meetings, provides annual risk report to Human Research Ethics Committee (HREC) and Melbourne Clinical Trials Committee (MCTC) and assesses AEs and serious and unexpected suspected adverse reaction with appropriate reporting to HREC and MCTC. They are responsible for maintenance of the database, budget administration, HREC updates and amendments and randomisation.
Statistics methods
Outcomes
The intervention arm will be compared against the SoC arm. Categorical variables will be summarised using frequency and percentage. Continuous variables will be summarised using mean and SD or median and IQR as appropriate. Restricted maximum likelihood regression will be used to compare both study arms AEs rates. Models will be extended to adjust for potential confounding factors including age, gender, ethnicity, diagnosis, treatment and stage as required. ADRs will be reported overall by type and severity and for each medication class.
Additional analysis
An interim analysis will be performed for the primary outcome once 50% of the sample size has been recruited (n=220). The purpose of this interim analysis will be to confirm that a reduction in ADR has not already been proven to a statistically significant point, thus being unethical to continue with the randomisation. However, in the absence of this, it will be to inform the final sample size based on the prevalence of aPGx and ADR prevalence.
Methods: monitoring
Data monitoring
Data monitoring committee
A data monitoring committee (DMC) has been established for the purposes of the interim analysis and monitoring data accuracy. Involvement in the DMC has ensured no members have conflicts of interest. Data monitoring is conducted weekly and reported back at a weekly trial meeting. The DMC will meet formally at the time of interim analysis.
Interim analysis and DMC
An interim analysis is performed on the primary endpoint when 50% of patients have been randomised and have completed the 3 months follow-up. The interim analysis performed by an independent statistician will provide a report to the DMC and the institute Human Research and Ethics Committee (HREC). The HREC and DMC will decide on the continuation of the trial.
Harms
An AE will be defined as any untoward medical occurrence in a subject without regard to the possibility of a causal relationship. As ADRs are noted as part of the study methodology, AEs are limited to those related to the intervention (extended pharmacogenetic results). All AEs will be collected and recorded in detail according to the Common Terminology Criteria for Adverse Events (V.5.0) after the subject has provided consent and enrolled in the study. The data will be collected by the ethics committee from The Royal Children’s Hospital, Melbourne and noted on the ClinicalTrials.gov Protocol Registration and Results System.
Auditing
Auditing is performed weekly. Auditing ensures compliance with % enrolment, release of SOC arm, re-enrolment of subjects as per Service Australia standards at 14 years of age and compliance with completing QoL and Ped-PRO-CTCAE surveys. A summary audit will be presented at the time of interim analysis to the DMC (at 50% of the inclusions) and at the end of the study. Reports of study progress are due yearly to the ethics committee of The Royal Children’s Hospital and at the time of the interim analysis. The auditing is performed by an independent research assistant, separate to the principal and associate investigators.
Ethics and dissemination
Research ethics approval
The ethics approval of the trial has been obtained from the Royal Children’s Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken assessment of the protocol and governance submission.
Protocol amendments
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes in study objectives, study design, patient population, sample sizes, study procedures or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be agreed on by the SC and approved by the ethics committee at The Royal Children’s Hospital prior to implementation and notification of participating site for site-specific approval.
Consent
Trained research assistants or academic pharmacists will introduce the trial to adolescent and young adult patients or parents of children who meet eligibility for the trial during outpatient visits or on ward rounds. Patients and parents will then have time to think about the study and also to discuss it with their primary consultant. Written informed consent from adolescent and young adult patients or parents of children willing to participate in the trial will be attained after a discussion of the specifics of the trial in line with the information statements. Information statements are provided in two forms: one for adolescent and young adult patients (online supplemental appendix E) and one for parent/guardians (online supplemental appendix F). In accordance with the National Statement,15 the Royal Children’s Hospital HREC considers it inappropriate to state a definite age at which the participant will be offered the opportunity to consent themselves; rather the individual level of maturity and corresponding capacity to be involved in the decision should be the deciding factor.
Confidentiality
Participant confidentiality is strictly held in trust by the PI, research staff and the sponsoring institution MCRI and their agents. This confidentiality is extended to cover clinical information relating to participating participants.
The trial protocol, documentation, data and all other information generated will be held in strict confidence. No information concerning the trial or the data will be released to any unauthorised third party, without prior written approval of the sponsoring institution. Authorised representatives of the sponsoring institution may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic or hospital) and pharmacy records for the participants in this trial. The Royal Children’s Hospital will permit access to such records.
All evaluation forms, reports and other records that leave the site will be identified only by the participant identification number (SID) to maintain participant confidentiality.
Clinical information will not be released without written permission of the participant, except as necessary for monitoring by HREC or regulatory agencies.
Patient and public involvement
Patients and public were first involved in the design of the research at the time of applying for funding through the Medical Research Future Fund. The protocol and grant application were developed with consumer participants from the Victorian Paediatric Cancer Consortium (VPCC) including consumer chief investigators on the grant application. Over the last 12 months, we have had three separate meetings with the VPCC Patient Advisory Group to inform on study progress, attain feedback on project methodology and consent.
Declaration of interest
There are no identified financial or other competing interests for any investigators participating in this trial.
Access to data
The PI and SC will oversee the intrastudy sharing process, at both the interim analysis and at the end of the trial.
The statistician will be given access to cleaned data and complete the analysis of the primary endpoint blinded. The health economics analyst will be given deidentified data of patients according to study number and these will be subdivided according to study arm. The analysis will then be performed for cost and QoL assessment.
Dissemination policy
Trial results
At the conclusion of the trial, participants will be emailed the trial results to provide an overview of the findings. Services Australia and PHRN will be sent a copy of any research papers prior to publication to confirm they are happy regarding their contributions to the project. MCRI holds the primary responsibility for publication of the results of the trial.
Ethics statements
Patient consent for publication
Acknowledgments
This study is endorsed by the Australian and New Zealand Children’s Oncology Group (ANZCHOG) and the Victorian Paediatric Cancer Consortium (VPCC). ANZCHOG provided access to experts to participate grant call and VPCC facilitated consumer participation in grant development and protocol development. We thank all of those who have contributed to the study. RC is supported by the Kids Cancer Project, The Royal Children’s Hospital Foundation, Victorian Paediatric Cancer Consortium, The Medical Research Future Fund and holds a Murdoch Children’s Research Institute (MCRI) Clinician Scientist Fellowship. DAE is a member of the Novo Nordisk Foundation Center for Stem Cell Medicine which is supported by a Novo Nordisk Foundation grant number NNF21CC0073729 and is supported by National Health and Medical Research Council of Australia (DAE), Heart Foundation of Australia and The Medical Research Future Fund. MCRI is supported by the Victorian Government’s Operational Infrastructure Support Program.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors The principal investigator for MARVEL is RC whose team contributed to the writing of the study. RC, BF, AH, TStenta and LC were involved in initial drafting. AH designed the bioinformatic workflow and pharmacogenomics report for the study. TSpelman contributed to statistical design and proposed statistical analysis. CM, DK, EW, RD and JS have contributed to refinement and editing of the protocol including designing expansion to the national cohort (EW, RD, MKM, RSK and SJ). DAE is laboratory head and has had oversight to the trial rollout and design. All authors contributed to the protocol development and/or edited and approved the final manuscript.
Funding MARVEL-PIC is funded through a nationally competitive Medical Research Future Fund Grant (Genomics Health Future Fund MRF/2024900). Preliminary pilot funding was obtained through the Kids Cancer Foundation.
Disclaimer This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.