Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study.

PURPOSE: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. METHODS: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb-July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. RESULTS: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32-81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7-8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months' treatment duration; median of 4 mm [IQR - 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month's duration of BrET. DISCUSSION: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.

Splinting for the non-operative management of developmental dysplasia of the hip (DDH) in children under six months of age.

BACKGROUND: Developmental dysplasia of the hip (DDH) describes the abnormal development of a hip in childhood, ranging from complete dislocation of the hip joint to subtle immaturity of a hip that is enlocated and stable within the socket. DDH occurs in around 10 per 1000 live births, though only one per 1000 are completely dislocated. There is variation in treatment pathways for DDH, which differs between hospitals and even between clinicians within the same hospital. The variation is related to the severity of dysplasia that is believed to require treatment, and the techniques used to treat dysplasia. OBJECTIVES: To determine the effectiveness of splinting and the optimal treatment strategy for the non-operative management of DDH in babies under six months of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, seven other electronic databases, and two trials registers up to November 2021. We also checked reference lists, contacted study authors, and handsearched relevant meetings abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs), including quasi-RCTs, as well as non-RCTs and cohort studies conducted after 1980 were included. Participants were babies with all severities of DDH who were under six months of age. Interventions included dynamic splints, static splints or double nappies (diapers), compared to no splinting or delayed splinting. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and performed risk of bias and GRADE assessments. The primary outcomes were: measurement of acetabular index at years one, two and five, as determined by radiographs (angle): the need for operative intervention to achieve reduction and to address dysplasia; and complications. We also investigated other outcomes highlighted by parents as important, including the bond between parent and child and the ability of mothers to breastfeed. MAIN RESULTS: We included six RCTs or quasi-RCTs (576 babies). These were supported by 16 non-RCTs (8237 babies). Five studies had non-commercial funding, three studies stated 'no funding' and 14 studies did not state funding source. The RCTs were generally at unclear risk of bias, although we judged three RCTs to be at high risk of bias for incomplete outcome data. The non-RCTs were of moderate and critical risk of bias. We did not undertake meta-analysis due to methodological and clinical differences between studies; instead, we have summarised the results narratively. Dynamic splinting versus delayed or no splinting Four RCTs and nine non-RCTs compared immediate dynamic splinting and delayed dynamic splinting or no splinting. Of the RCTs, two considered stable hips and one considered unstable (dislocatable) hips and one jointly considered unstable and stable hips. No studies considered only dislocated hips. Two RCTs (265 babies, very low-certainty evidence) reported acetabular index at one year amongst stable or dislocatable hips. Both studies found there may be no evidence of a difference in splinting stable hips at first diagnosis compared to a strategy of active surveillance: one reported a mean difference (MD) of 0.10 (95% confidence interval (CI) -0.74 to 0.94), and the other an MD of 0.20 (95% CI -1.65 to 2.05). Two RCTs of stable hips (181 babies, very low-certainty evidence) reported there may be no evidence of a difference between groups for acetabular index at two years: one study reported an MD of -1.90 (95% CI -4.76 to 0.96), and another study reported an MD of -0.10 (95% CI -1.93 to 1.73), but did not take into account hips from the same child. No study reported data at five years. Four RCTs (434 babies, very low-certainty evidence) reported the need for surgical intervention. Three studies reported that no surgical interventions occurred. In the remaining study, two babies in the dynamic splinting group developed instability and were subsequently treated surgically. This study did not explicitly state if this treatment was to achieve concentric reduction or address residual dysplasia. Three RCTs (390 babies, very low-certainty evidence) reported no complications (avascular necrosis and femoral nerve palsy). Dynamic splinting versus static splinting One RCT and five non-RCTs compared dynamic versus static splinting. The RCT (118 hips) reported no occurrences of avascular necrosis (very low-certainty evidence) and did not report radiological outcomes or need for operative intervention. One quasi-RCT compared double nappies versus delayed or no splinting but reported no outcomes of interest. Other comparisons No RCTs compared static splinting versus delayed or no splinting or staged weaning versus immediate removal. AUTHORS' CONCLUSIONS: There is a paucity of RCT evidence for splinting for the non-operative management of DDH: we included only six RCTs with 576 babies. Moreover, there was considerable heterogeneity between the studies, precluding meta-analysis. We judged the RCT evidence for all primary outcomes as being of very low certainty, meaning we are very uncertain about the true effects. Results from individual studies provide limited evidence of intervention effects on different severities of DDH. Amongst stable dysplastic hips, there was no evidence to suggest that treatment at any stage expedited the development of the acetabulum. For dislocatable hips, a delay in treatment onset to six weeks does not appear to result in any evidence of a difference in the development of the acetabulum at one year or increased risk of surgery. However, delayed splinting may reduce the number of babies requiring treatment with a harness. No RCTs compared static splinting with delayed or no splinting, staged weaning versus immediate removal or double nappies versus delayed or no splinting. There were few operative interventions or complications amongst the RCTs and the non-randomised studies. There's no apparent signal to indicate a higher frequency of either outcome in either intervention group. Given the frequency of this disease, and the fact that many countries undertake mandatory DDH screening, there is a clear need to develop an evidence-based pathway for treatment. Particular uncertainties requiring future research are the effectiveness of splinting amongst stable dysplastic hips, the optimal timing for the onset of splinting, the optimal type of splint to use and the need for 'weaning of splints'. Only once a robust pathway for treatment is established, can we properly assess the cost-effectiveness of screening interventions for DDH.

Development of a core outcome set for basal cell carcinoma.

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

Establishment of a core outcome set for burn care research: development and international consensus.

Objective: To develop a core outcome set for international burn research. Design: Development and international consensus, from April 2017 to November 2019. Methods: Candidate outcomes were identified from systematic reviews and stakeholder interviews. Through a Delphi survey, international clinicians, researchers, and UK patients prioritised outcomes. Anonymised feedback aimed to achieve consensus. Pre-defined criteria for retaining outcomes were agreed. A consensus meeting with voting was held to finalise the core outcome set. Results: Data source examination identified 1021 unique outcomes grouped into 88 candidate outcomes. Stakeholders in round 1 of the survey, included 668 health professionals from 77 countries (18% from low or low middle income countries) and 126 UK patients or carers. After round 1, one outcome was discarded, and 13 new outcomes added. After round 2, 69 items were discarded, leaving 31 outcomes for the consensus meeting. Outcome merging and voting, in two rounds, with prespecified thresholds agreed seven core outcomes: death, specified complications, ability to do daily tasks, wound healing, neuropathic pain and itch, psychological wellbeing, and return to school or work. Conclusions: This core outcome set caters for global burn research, and future trials are recommended to include measures of these outcomes.

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study.

BACKGROUND: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. METHODS: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting. FINDINGS: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. CONCLUSIONS: The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

Core Outcome Set for Actinic Keratosis Clinical Trials.

Importance: Although various treatments have been found in clinical trials to be effective in treating actinic keratosis (AK), researchers often report different outcomes. Heterogeneous outcome reporting precludes the comparison of results across studies and impedes the synthesis of treatment effectiveness in systematic reviews. Objective: To establish an international core outcome set for all clinical studies on AK treatment using systematic literature review and a Delphi consensus process. Evidence Review: Survey study with a formal consensus process. The keywords actinic keratosis and treatment were searched in PubMed, Embase, CINAHL, and the Cochrane Library to identify English-language studies investigating AK treatments published between January 1, 1980, and July 13, 2015. Physician and patient stakeholders were nominated to participate in Delphi surveys by the Measurement of Priority Outcome Variables in Dermatologic Surgery Steering Committee members. All participants from the first round were invited to participate in the second round. Outcomes reported in randomized controlled clinical trials on AK treatment were rated via web-based e-Delphi consensus surveys. Stakeholders were asked to assess the relative importance of each outcome in 2 Delphi survey rounds. Outcomes were provisionally included, pending the final consensus conference, if at least 70% of patient or physician stakeholders rated the outcome as critically important in 1 or both Delphi rounds and the outcome received a mean score of 7.5 from either stakeholder group. Data analysis was performed from November 5, 2018, to February 27, 2019. Findings: A total of 516 outcomes were identified by reviewing the literature and surveying key stakeholder groups. After deduplication and combination of similar outcomes, 137 of the 516 outcomes were included in the Delphi surveys. Twenty-one physicians and 12 patients participated in round 1 of the eDelphi survey, with 17 physicians (81%) retained and 12 patients (100%) retained in round 2. Of the 137 candidate outcomes, 9 met a priori Delphi consensus criteria, and 6 were included in the final outcomes set after a consensus meeting: complete clearance of AKs, percentage of AKs cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and recurrence rate. It was recommended that treatment response be assessed at 2 to 4 months and recurrence at 6 to 12 months, with the AK rate of progression to cutaneous squamous cell carcinoma reported whenever long-term follow-up was possible. Conclusions and Relevance: Consensus was reached regarding a core outcome set for AK trials. Further research may help determine the specific outcome measures used to assess each of these outcomes.

Value Assessment and Quantitative Benefit-Risk Modelling of Biosimilar Infliximab for Crohn's Disease.

BACKGROUND AND OBJECTIVE: Regulatory approval of biosimilars often depends on extrapolating evidence from one clinical indication to all of those of the originator biologic. We aimed to develop a quantitative benefit-risk analysis to assess whether the resulting increase in the uncertainty in the clinical performance of biosimilars (i.e. risk) may be countered by their lower pricing (benefit). METHODS: A 1-year decision-analytic model was developed for the biosimilar infliximab (Inflectra®) for Crohn's disease. The perspective was that of the National Health Service in the UK and costs were valued to 2015/16. A hypothetical cohort of biologic-naïve patients with moderate-to-severe Crohn's disease was simulated through the model. Immunogenicity to infliximab was a key modifier, influencing rates of non-response and infusion reactions. Net health benefit was estimated based on quality-adjusted life-years. A range of sensitivity analyses tested the robustness of the results and explored how the biosimilar price must respond to varying immunogenicity to remain the preferred option. RESULTS: The base-case analysis predicted a positive incremental net health benefit of 0.04 (95% central range 0.00-0.09) favouring the biosimilar, based on 0.803 quality-adjusted life-years, and costs of £18,087 and £19,176 for the biosimilar and originator, respectively. Two-way sensitivity analyses suggested that if 50% of patients developed antibodies, the value-based price of £410 per vial must be lower than that of the originator (£420), but remain higher than the actual market price (£378). CONCLUSIONS: The model supports the use of Inflecta® for Crohn's disease in the UK, and provides a framework for the quantitative evaluation of biosimilars in the context of a health technology assessment. Value-based pricing using this methodology could protect health systems from the potential risks of biosimilars where they are untested in the approved populations.

A Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints: the COSGROVE study.

BACKGROUND: Fetal growth restriction refers to a fetus that does not reach its genetically predetermined growth potential. It is well-recognized that growth-restricted fetuses are at increased risk of both short- and long-term adverse outcomes. Systematic evaluation of the evidence from clinical trials of fetal growth restriction is often difficult because of variation in the outcomes that are measured and reported. The development of core outcome sets for fetal growth restriction studies would enable future trials to measure similar meaningful outcomes. OBJECTIVE: The purpose of this study was to develop core outcome sets for trials of prevention or treatment of fetal growth restriction. STUDY DESIGN: This was a Delphi consensus study. A comprehensive literature review was conducted to identify outcomes that were reported in studies of prevention or treatment of fetal growth restriction. All outcomes were presented for prioritization to key stakeholders (135 healthcare providers, 68 researchers/academics, and 35 members of the public) in 3 rounds of online Delphi surveys. A priori consensus criteria were used to reach agreement on the final outcomes for inclusion in the core outcome set at a face-to-face meeting with 5 healthcare providers, 5 researchers/academics, and 6 maternity service users. RESULTS: In total, 22 outcomes were included in the final core outcome set. These outcomes were grouped under 4 domains: maternal (n=4), fetal (n=1), neonatal (n=12), and childhood (n=5). CONCLUSION: The Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints study identified a large number of potentially relevant outcomes and then reached consensus on those factors that, as a minimum, should be measured and reported in all future trials of prevention or treatment of fetal growth restriction. This will enable future trials to measure similar meaningful outcomes and to ensure that findings from different studies can be compared and combined.

Improvement was needed in the standards of development for cancer core outcome sets.

OBJECTIVE: The Core Outcome Set-STAndards for Development (COS-STAD) contains 11 standards (12 criteria) that are deemed to be the minimum design recommendations for all core outcome set (COS) development projects. Cancer is currently the disease area with the highest number of published COSs and is a major cause of worldwide morbidity and mortality. The aim of this study was to provide a baseline of cancer COS standards. STUDY DESIGN AND SETTING: Systematic reviews of COSs have identified 307 published COS studies. Cancer COSs were eligible for inclusion. Two reviewers independently assessed each of the COSs against the 12 criteria. RESULTS: Forty-nine cancer COSs were included; none met all 12 criteria representing the 11 minimum standards assessed in this study (range = 4-11 criteria, median = 6 criteria). All studies met the four scope standards, eight (16%) met all three standards for stakeholders involved, and two (4%) met all four standards for consensus process standards. CONCLUSION: With the exception of "scope" specification, there is much need for improvement. Poor reporting often made it challenging to assess whether minimum standards were met. The consensus process criteria were most difficult to assess, particularly those that required an assessment of being a priori. This is the first application of COS-STAD criteria to studies that have developed COSs and provides a baseline of cancer COS standards of development.

Systematic review: outcomes and adverse events from randomised trials in Crohn's disease.

BACKGROUND: The suitability of disease activity indices has been challenged, with growing interest in objective measures of inflammation. AIM: To undertake a systematic review of efficacy and safety outcomes in placebo-controlled randomised controlled trials (RCTs) of patients with Crohn's disease. METHODS: MEDLINE, EMBASE, CINAHL and Cochrane Library were searched until November 2015, for RCTs of adult Crohn's disease patients treated with medical or surgical therapies. Data on efficacy and safety outcomes, end-point definitions, and measurement instruments were extracted and stratified by publication date (pre-2009 and 2009 onwards). RESULTS: One hundred and eighty-one RCTs (110 induction and 71 maintenance) were identified, including 23 850 patients. About 92.3% reported clinical efficacy endpoints. The Crohn's Disease Activity Index (CDAI) dominated, defining clinical response or remission in 63.5% of trials (35 definitions of response or remission). CDAI < 150 was the commonest endpoint, but reporting reduced between periods (46.4%-41.1%), whilst use of CDAI100 increased (16.8%-30.4%). Fistula studies most commonly reported fistula closure (9, 90.0%). Reporting of biomarker, endoscopy and histology endpoints increased overall (33.3%-40.6%, 14.4%-30.4% and 3.2%-12.5%, respectively), but were heterogeneous and rarely reported in fistula trials. Patient-reported outcome measures were reported in 41.4% of trials and safety endpoints in 35.4%. Many of the common adverse events relate to disease exacerbation or treatment failure. CONCLUSIONS: Trial endpoints vary across studies, over time and are distinct in fistula studies. Despite growth in reporting of objective measures of inflammation and in patient-reported outcome measures, there is a lack of standardisation. This confirms the need for a core outcome set for comparative effectiveness research in Crohn's disease.

Management of medial humeral epicondyle fractures in children: a structured review protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey.

BACKGROUND: Medial humeral epicondyle fractures of the elbow are one of the most common injuries in childhood and often require surgery. There are currently no standardised outcome measures to assess progress after an elbow injury in a child. Wide variation in currently reported outcomes makes comparison of treatment difficult. This study aims to identify outcome measures that have previously been reported in studies evaluating the management of medial epicondyle fractures in children and to facilitate the development of a consensus core outcome set (COS) suitable for use in all future studies of medial humeral epicondyle fractures in children. METHODS/DESIGN: This study will include a systematic review of the academic literature to identify a list of outcome measures that have previously been reported. The list of outcome measures will be used in a consensus setting exercise with focus groups of key stakeholders to identify key outcomes. A Delphi process to include two rounds will then be used to define the most important outcomes to all stakeholders forming the COS. DISCUSSION: Core outcomes represent the minimum expected data reported for a specific condition and will improve the quality of future studies reducing bias, allowing easier comparison and enhancing opportunities for larger meta-analysis. It is anticipated that this COS will form part of the feasibility to a National Institute for Health Research (NIHR) Health Technology Assessment (HTA)-funded trial concerning the management of elbow fractures in children. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials Initiative (COMET), registration number: 949 . Registered on 17 January 2017. Prospero International prospective register of systematic reviews, registration number: CRD 42017057912 . Registered on 16 April 2017.

A randomized trial comparing three Delphi feedback strategies found no evidence of a difference in a setting with high initial agreement.

OBJECTIVES: The objective of the study was to explore the impact of different feedback strategies on (1) subsequent agreement and (2) variability in Delphi studies. STUDY DESIGN AND SETTING: A two-round Delphi survey, with a list of outcomes generated from the results of a systematic review and interviews, was undertaken while developing a core outcomes set for prostate cancer including two stakeholder groups (health professionals and patients). Seventy-nine outcomes were scored on a scale of one (not important) to nine (critically important). Participants were randomized in round 2 to receive round 1 feedback from peers only, multiple stakeholders separately, or multiple stakeholders combined. RESULTS: Agreement on outcomes retained for all feedback groups was high (peer: 92%, multiple separate: 90%, multiple combined: 84%). There were no statistically significant reduction in variability for peer vs. multiple separate (0.016 [-0.035, 0.067]; P = 0.529), or multiple separate vs. multiple combined feedback (0.063 [-0.003, 0.129]; P = 0.062). Peer feedback statistically significantly reduced variability compared with multiple combined feedback (0.079 [0.001, 0.157]; P = 0.046). CONCLUSIONS: We found no evidence of a difference between different feedback strategies in terms of the number of outcomes retained or reduction in variability of opinion. However, this may be explained by the high level of existing agreement in round 1. Further methodological studies nested within Delphi surveys will help clarify the best strategy.

PAEDIATRIC ADVERSE DRUG REACTIONS (ADRS): A COMPARISON OF A NEWLY DEVELOPED AVOIDABILITY TOOL TO EXISTING HALLAS ASSESSMENTS.

AIM: To compare a newly developed avoidability assessment tool (AAT) to existing Hallas assessments1 for a set of paediatric ADR cases. METHOD: The new AAT was employed to assess 249 case reports of ADRs causing admission to hospital. The case reports contained a description of the ADR, details of suspected and concurrent medication and past medical history. Each case report was independently assessed and an avoidability category assigned. For ADRs categorised as either 'possibly' or 'definitely avoidable' a rationale was recorded. A second reviewer independently assessed a purposive sample (10%) for validation and quality assurance purposes.The final outcome was then compared to the Hallas assessments (1) previously completed as part of another study, which was carried out in a consensus group setting. Both tools used categorical scores with the same four point ordinal scale 'definitely avoidable', 'possibly avoidable', 'not avoidable' and 'unassessable'. RESULTS: Assessment of the 249 ADR case reports using the new AAT found that 19.3% were either possibly or definitely avoidable. This figure increased to almost 32% for the non-oncology cases (129/249) and decreased to 5.8% for the oncology cases (120/249). This was similar to the Hallas results (1), where overall, 22% of ADRs were deemed either possibly or definitely avoidable.Percentage exact agreement (%EA) was 90% overall; when subcategorised into oncology and non-oncology cases the %EA was found to be 94.2% and 86% respectively. Percentage extreme disagreement (%ED) was 0.8%. The kappa score was 0.71 (95% CI 0.60-0.82) for all cases, 0.54 (95% CI 0.40-0.68) for the oncology cases and 0.73 (95% CI 0.58-0.88) for the non-oncology cases. In total there were 25/249 cases with disagreement. %EA agreement from the validation check was 72%. CONCLUSION: Assessment with the new AAT showed that approximately 19% of all cases were either possibly or definitely avoidable. This was comparable to the Hallas assessments (1). The sub-categorisation of the analysis into oncology and non-oncology cases showed a change in the number of avoidable cases. The avoidability rate increased to almost 32% for the non-oncology cases and decreased to 5.8% for the oncology cases. The reason for this marked difference may be explained by the nature of the oncology ADRs. The most common oncology reactions were neutropenia, thrombocytopenia and anaemia; these are often expected and largely 'not avoidable' given the benefit risk ratio.The AAT was designed specifically for use in paediatrics following difficulty using other tools including Hallas (1). The AAT refers to guidelines and patient history rather than to abstract concepts such as "present-day knowledge of good medical practice" and "effort exceeding the obligatory demands" as per Hallas (1). Further work to identify potentially avoidable ADRs and strategies to prevent them is needed.

The Importance of Integration of Stakeholder Views in Core Outcome Set Development: Otitis Media with Effusion in Children with Cleft Palate.

BACKGROUND: Approximately 75% of children with cleft palate (CP) have Otitis Media with Effusion (OME) histories. Evidence for the effective management of OME in these children is lacking. The inconsistency in outcome measurement in previous studies has led to a call for the development of a Core Outcome Set (COS). Despite the increase in the number of published COS, involvement of patients in the COS development process, and methods to integrate the views of patients and health professionals, to date have been limited. METHODS AND FINDINGS: A list of outcomes measured in previous research was identified through reviewing the literature. Opinion on the importance of each of these outcomes was then sought from key stakeholders: Ear, Nose and Throat (ENT) surgeons, audiologists, cleft surgeons, speech and language therapists, specialist cleft nurses, psychologists, parents and children. The opinion of health professionals was sought in a three round Delphi survey where participants were asked to score each outcome using a bespoke online system. Parents and children were also asked to score outcomes in a survey and provided an in-depth insight into having OME through semi-structured interviews. The results of the Delphi survey, interviews and parent/patient survey were brought together in a final consensus meeting with representation from all stakeholders. A final set of eleven outcomes reached the definition of "consensus in" to form the recommended COS: hearing; chronic otitis media (COM); OME; receptive language skills; speech development; psycho social development; acute otitis media (AOM); cholesteatoma; side effects of treatment; listening skills; otalgia. CONCLUSIONS: We have produced a recommendation about the outcomes that should be measured, as a minimum, in studies of the management of OME in children with CP. The development process included input from key stakeholders and used novel methodology to integrate the opinion of healthcare professionals, parents and children.

Clinical coding of prospectively identified paediatric adverse drug reactions--a retrospective review of patient records.

BACKGROUND: National Health Service (NHS) hospitals in the UK use a system of coding for patient episodes. The coding system used is the International Classification of Disease (ICD-10). There are ICD-10 codes which may be associated with adverse drug reactions (ADRs) and there is a possibility of using these codes for ADR surveillance. This study aimed to determine whether ADRs prospectively identified in children admitted to a paediatric hospital were coded appropriately using ICD-10. METHODS: The electronic admission abstract for each patient with at least one ADR was reviewed. A record was made of whether the ADR(s) had been coded using ICD-10. RESULTS: Of 241 ADRs, 76 (31.5%) were coded using at least one ICD-10 ADR code. Of the oncology ADRs, 70/115 (61%) were coded using an ICD-10 ADR code compared with 6/126 (4.8%) non-oncology ADRs (difference in proportions 56%, 95% CI 46.2% to 65.8%; p < 0.001). CONCLUSIONS: The majority of ADRs detected in a prospective study at a paediatric centre would not have been identified if the study had relied on ICD-10 codes as a single means of detection. Data derived from administrative healthcare databases are not reliable for identifying ADRs by themselves, but may complement other methods of detection.

Adverse drug reactions and off-label and unlicensed medicines in children: a prospective cohort study of unplanned admissions to a paediatric hospital.

AIMS: To examine the impact of off-label and unlicensed (OLUL) prescribing on adverse drug reactions (ADRs) causing unplanned admissions to a paediatric hospital. METHODS: Prescription data from a 12 month prospective cohort study of ADRs detected in children admitted to a paediatric hospital were scrutinized. The relative risk for off-label and unlicensed medicines being implicated in an ADR was calculated. Logistic regression analyses were carried out with exposure to off-label and unlicensed medicines and number of off-label and unlicensed medicines administered as predictor variables. RESULTS: Off-label and unlicensed medicines were more likely to be implicated in an ADR than authorized medicines (relative risk 1.67, 95% CI 1.38, 2.02, P < 0.001). There was a 25% increase in ADR risk (95% CI 1.16, 1.35, P < 0.001) with each additional authorized medicine and 23% (95% CI 1.10, 1.36, P < 0.001) with each additional off-label or unlicensed medicine. Logistic regression analysis focusing on non-oncology patients demonstrated that the number of authorized medicines (odds ratio 1.33, 95% CI 1.23, 1.44, P < 0.001), but not the number of off-label and unlicensed medicine courses, was a predictor of ADR risk. CONCLUSIONS: In a heterogeneous population of children admitted to a secondary/tertiary hospital, off-label and unlicensed medicines are more likely to be implicated in an ADR than authorized medicines. This was largely driven by ADRs related to drugs used in oncological practice, where the usage of off-label or unlicensed medicines was associated with a higher ADR risk than in non-oncological areas.