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Patient-reported outcomes (PROs), such as symptoms, functioning, and other health-related quality-of-life concepts are gaining a more prominent role in the benefit–risk assessment of cancer therapies. However, varying ways of analysing, presenting, and interpreting PRO data could lead to erroneous and inconsistent decisions on the part of stakeholders, adversely affecting patient care and outcomes. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) Consortium builds on the existing SISAQOL work to establish recommendations on design, analysis, presentation, and interpretation for PRO data in cancer clinical trials, with an expanded set of topics, including more in-depth recommendations for randomised controlled trials and single-arm studies, and for defining clinically meaningful change. This Policy Review presents international stakeholder views on the need for SISAQOL-IMI, the agreed on and prioritised set of PRO objectives, and a roadmap to ensure that international consensus recommendations are achieved.

IntroductionEarly phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.Methods and analysisA methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.Ethics and disseminationThis project was approved by ICR’s Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.Registration detailsSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

This article summarizes the discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum that took place on December 10, 2020 and was organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group, in coordination with the U.S. FDA Oncology Center of Excellence. Diverse stakeholders including experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on the use of nonconcurrent control in Master Protocols for oncology trials. While the use of nonconcurrent control with the concurrent control may increase the power of detecting the therapeutic difference between a treatment and the control, the panelists had diverse opinion on the statistical approaches for modeling nonconcurrent and concurrent controls. Some were more concerned about the temporality of the nonconcurrent control and bias introduced by different confounders related to time, for example, changes in standard of care, changes in patient population, changes in recruiting strategies, changes in assessment of endpoints. Nevertheless, in some situations such as when the recruitment is extremely challenging for a rare disease, the panelists concluded that the use of a nonconcurrent control can be justified.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

Objectives To explore current delays in diagnosis of retinoblastoma (Rb) and effect on outcome with comparison to a study from the 1990s. Setting Primary, secondary, tertiary care: majority from South of England. Participants A retrospective analysis of 93 new referrals of sporadic (non-familial) Rb to a specialist Rb unit in London, UK from January 2006 to February 2014. Primary and secondary outcomes International Intraocular Retinoblastoma Classification, lag times including parental delay and healthcare professional delay, patients requiring enucleation and requirement of adjuvant chemotherapy postenucleation (high-risk Rb). Results During the study period, 29% presented via accident and emergency (A&E). The median referral time from symptom onset to visiting primary care (PC) was 28 days and PC to ophthalmologist 3 days (range 0–181 days). The median time from local ophthalmologist to the Rb Unit was 6 days (0–33). No significant correlation was found between delay and International Classification of Retinoblastoma grade (p>0.05) or between postenucleation adjuvant chemotherapy and enucleation groups (p>0.05). Less enucleations (60%) are being performed compared with the previous study (81%) (p=0.0015). Conclusions Parents are attending A&E more compared with the 1990s and this may reflect the effect of public awareness campaigns. More eyes are being salvaged despite a similar number of children requiring adjuvant chemotherapy. High-risk Rb and Group E eyes do not correlate with increased lag time in the UK. Other determinants such as tumour biology may be more relevant.

Aims and methodTo develop a programme to help undergraduate medical students and postgraduate trainees to improve their skills in communicating with people with intellectual disabilities through teaching sessions that had input from simulated patients with intellectual disabilities. We conducted four sessions of training for 47 undergraduate 4th-year medical students. The training involved a multiprofessional taught session followed by a clinical scenario role-play with simulated patients who were people with intellectual disabilities. The training was assessed by completing the healthcare provider questionnaire before and after the training.ResultsThere were improvements in the students' perceived skill, comfort and the type of clinical approach across all three scenarios.Clinical implicationsBy involving people with intellectual disabilities in training medical students there has been a significant improvement in students' communication skills in areas of perceived skills, comfort and type of clinical approach which will raise the quality of care provided by them in the future.

BackgroundDown syndrome is associated with specific cognitive deficits. Alongside this, older adults with Down syndrome are a high risk group for dementia. The Arizona Cognitive Test Battery (ACTB), a cognitive assessment battery specifically developed for use with individuals with Down syndrome, has been proposed for use as outcome measures for clinical trials in this population. It has not been validated in older adults with Down syndrome. This study aims to assess the use and validity of the ACTB in older adults with Down syndrome.MethodsParticipants with Down syndrome aged 45 and over were assessed using the ACTB, standard tabletop tests and informant ratings.ResultsAssessment outcomes of 49 participants were analysed. Of these, 19 (39%) had a diagnosis of dementia or possible dementia. Most participants were able to attempt most of the tasks, although some tasks had high floor effects (including CANTAB Intra-Extra Dimensional shift stages completed and Modified Dots Task). Of the ACTB tasks, statistically significant differences were observed between the dementia and no dementia groups on CANTAB Simple Reaction Time median latency, NEPSY Visuomotor Precision—Car and Motorbike and CANTAB Paired Associates Learning stages completed. No significant differences were observed for CANTAB Intra-Extra Dimensional Shift, Modified Dots Task, Finger Sequencing, NEPSY Visuomotor precision—Train and Car and CANTAB Paired Associates Learning first trial memory score. Several of the tasks in the ACTB can be used in older adults with Down syndrome and have mild to moderate concurrent validity when compared to tabletop tests and informant ratings, although this varies on a test by test basis.ConclusionsOverall, scores for a number of tests in the ACTB were similar when comparing dementia and no dementia groups of older adults with Down syndrome, suggesting that it would not be an appropriate outcome measure of cognitive function for clinical trials of dementia treatments without further modification and validation.

We conducted a five stage pilot study which initially consisted of a review of 75 case notes of people attending an emergency department (ED) in an inner London Teaching Hospital with musculoskeletal (MSK) low back pain (LBP). This review highlighted inconsistencies in how they were assessed and managed across and within different staff groups. We found patient documentation was often incomplete and that a biomedical model approach to the management of these patients was common. As a result, four further stages in the project were conducted. Our primary aim was to evaluate the impact of implementing a locally developed quality improvement intervention for the assessment and treatment of MSK LBP in this ED. Secondary aims were to explore the user experience of the new pathway, measured by the patient experience questionnaire (PEQ), and any associated health economic costs of changes in practice. The quality improvement intervention consisted of an evidence based low back pain pathway (EBLBPP), a staff educational program, and a patient education booklet. We undertook a retrospective baseline audit of 100 clinical records of patients was undertaken prior to the instigation of the quality improvement intervention, and four months post implementation. The pre-defined variables of interest were: documentation of the case history, examination, classification of back pain (and if correct), prescribed management and if the documentation was compliant with medico-legal standards. All patients in the study were sent a PEQ to complete and return in a self-addressed envelope. Estimated health costs associated with each patient episode of care were calculated including re-attendance episodes for any people presenting with MSK LBP within a four week period. There was a significant improvement in all areas evaluated post implementation in all groups (simple, referred and simple, referred and serious spinal pathology combined). In particular; screening for red flags (22%) and biopsychosocial factors (29%), as well as noting the prevalence of previous symptoms (44%), observation of the painful area (57%), and analysis classification (59%) at a at 95% confidence interval (CI). In terms of management, an increase in adherence to the analgesic ladder, patients receiving reassurance and appropriate referral back to their GP’s increased 45%, 23% and 44% at 95% CI respectively. Unfortunately, there was insufficient data to draw any meaningful conclusions from the patient experience data due to a low response rate. In conclusion, the introduction of the EBLBPP, patient education leaflet and teaching training for staff involved in the treatment of MSK LBP patients has improved the quality and consistency of the documented assessment and subsequent management of MSK LBP patients.