Outcome selection for tissue-agnostic drug trials for immune-mediated inflammatory diseases: a systematic review of core outcome sets and regulatory guidance

Background Tissue-agnostic drug development provides a paradigm shift in precision medicine and requires innovative trial designs. However, outcome selection for such trials can prove challenging. The objectives of this review were to: Identify and map core outcome sets (COS), across 11 immune-mediated inflammatory diseases (IMIDs) in order to facilitate the selection of relevant outcomes across the conditions for innovative trials of tissue-agnostic drug therapies. Compare outcomes or endpoints recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to identify and highlight similarities and differences. Methods The Core Outcome Measures in Effectiveness Trials (COMET), International Consortium for Health Outcomes Measurement (ICHOM), FDA and EMA databases were searched from inception to 28th December 2019. Two reviewers independently screened titles and abstracts of retrieved entries and conducted the subsequent full text screening. Hand searching of the reference lists and citation searching of the selected publications was conducted. The methodological quality of the included peer-reviewed articles was independently assessed by the reviewers based on the items of the COS–Standards for Development recommendations (COS–STAD) checklist. Core outcomes from the included publications were extracted and mapped across studies and conditions. Regulatory guidance from FDA and EMA, where available for clinical trials for the IMIDs, were obtained from their databases and recommendations on outcomes to measure directly compared. Results Forty-four COS publications were included in the final analysis. Outcomes such as disease activity, pain, fatigue, quality of life, physical function, work limitation/productivity, steroid use and biomarkers were recommended across majority of the conditions. There were significant similarities and differences in FDA and EMA recommendations. The only instance where either regulatory body directly referenced a COS was for jSLE—both referenced the Paediatric Rheumatology International Trials Organization (PRINTO) COS. Conclusions The findings from this systematic review provide valuable information to inform outcome selection in tissue-agnostic trials for IMIDs. There is a need for increased collaboration between regulators and COS developers and inclusion of regulators as key stakeholders in COS development to enhance the quality of COS. Trial registration Not registered.

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

Long lease real estate – a revised role for real estate in pension fund portfolios

PurposeLong lease real estate funds (over £15bn in Q3 2020) have emerged as an increasingly important part of UK pension fund real estate portfolios. This paper explores the reasons for their dramatic growth, their characteristics and performance.Design/methodology/approachThis study uses data for the period 2004–2020 collected directly from fund managers and from AREF/MSCI and empirical analysis to explore their characteristics and performance.FindingsPension fund de-risking and regulatory guidance have supported the dramatic growth of long lease real estate funds. Long lease real estate funds have delivered strong risk-adjusted returns relative to both balanced property funds (with shorter lease terms) and the wider property market. This relative performance has been particularly strong when wider property market performance has been weak. Long lease funds have objectives aligned with liability matching and their performance suggests they are lower risk (more bond-like) investments. In addition, our analysis highlights they are far less responsive to the wider property market than balanced funds. However, they are not significantly different from balanced property funds in terms of their short-term relationship with gilt yield movements.Practical implicationsFor pension funds and other investors the paper highlights that long lease real estate funds offer a different exposure than balanced property funds. Long lease funds have objectives more closely aligned to the overall objectives for pension fund investment but are not significantly more reliable than balanced property funds in the short-term as a liability hedge. For real estate fund managers, occupiers, developers and others active in the real estate market, the paper highlights why these funds have been (and are likely to remain) attractive to investors leading to substantial demand for long lease real estate investments.Originality/valueThis is the first study to review this increasingly important part of the UK real estate fund universe.

Development of the Near Vision Presbyopia Task-based Questionnaire for use in evaluating the impact of presbyopia

Background Presbyopia is a progressive condition that reduces the eye’s ability to focus on near objects with increasing age. After a systematic literature review identified no existing presbyopia-specific patient-reported outcome (PRO) instruments meeting regulatory guidance, a new PRO instrument, the Near Vision Presbyopia Task-based Questionnaire (NVPTQ), was developed. Results To explore the patient experience with presbyopia, concept elicitation interviews were conducted with 20 presbyopic participants. The most frequently reported impacts were difficulty with reading menus/books/newspapers/magazines, reading on a cell phone/caller ID, and reading small print. Based on these results, a task-based PRO instrument (the NVPTQ) was developed instructing participants to complete four near-vision, paper-based reading tasks (book, newspaper, nutrition label, menu) under standardized settings, and subsequently assess their vision-related reading ability and associated satisfaction. The draft NVPTQ was cognitively debriefed with a sample of 20 presbyopes, which demonstrated that most participants interpreted the items as intended and endorsed the relevance of the concepts being assessed. After the qualitative research, the draft instrument was psychometrically tested using data from a Phase 2 study. Based on item-level analyses, all items in the NVPTQ demonstrated expected response option patterns and lacked substantial floor or ceiling effects. The reliability, validity, and responsiveness of the NVPTQ Performance and Satisfaction domain scores were assessed. All domains scores had large Cronbach’s coefficient α values and good test–retest statistics, indicating that the scores are internally consistent and produce stable values over time. The pattern of correlations with a concurrent measure of visual functioning (National Eye Institute Visual Function Questionnaire 25) demonstrated that the NVPTQ domain scores were related to an alternative assessment of near-vision activities. The NVPTQ domain scores were able to distinguish between groups that were known to differ on the clinical outcome of uncorrected near visual acuity, supporting the construct validity of these scores. The NVPTQ domain scores showed evidence of responsiveness to change by being able to distinguish between groups defined as improved and not improved based on patient-reported and clinical outcomes. Conclusions This research has resulted in a content-valid and psychometrically sound instrument designed to evaluate vision-related reading ability and satisfaction with vision-related reading ability. Trial registration: ClinicalTrials.gov NCT02780115. Registered 23 May 2016, https://www.clinicaltrials.gov/ct2/show/NCT02780115?term=NCT02780115&draw=2&rank=1.

Informed consent and assent guide for paediatric clinical trials in Europe

ObjectiveClinical trial sponsors spend considerable resources preparing informed consent (IC) and assent documentation for multinational paediatric clinical trial applications in Europe due to the limited and dispersed patient populations, the variation of national legal and ethical requirements, and the lack of detailed guidance. The aim of this study was to design new easy-to-use guide publicly available on European Medicines Agency’s, Enpr-EMA website for all stakeholders.MethodsCurrent EU legal, ethical and regulatory guidance for paediatric clinical trials were collated, analysed and divided into 30 subject elements in two tables. The European Network of Young Person’s Advisory Group reviewed the data and provided specific comments. A three-level recommendation using ‘traffic light’ symbols was designed for four age groups of children, according to relevance and the requirements.ResultsA single guide document includes two tables: (1) general information and (2) trial-specific information. In the age group of 6–9 years old, 92% of the trial-specific subject elements can be or should be included in the IC discussion. Even in the youngest possible age group (2–5 years old children), the number of elements considered was, on average, 52%.ConclusionThe EU Clinical Trial Regulation (2014) does not contain specific requirements exclusively for paediatric clinical trials. This work is the first to extensively collate all the current legal, regulatory and ethical documentation on the IC process, together with input from adolescents. This guide may increase the ethical standards in paediatric clinical trials.

Experiences of Rural and Urban Assisted Living Communities in Oregon During COVID-19 Pandemic

This study presents findings on the impact of the COVID-19 pandemic as reported by a representative sample of Oregon assisted living communities (AL) between December 2020 and March 2021. Of the 559 AL eligible to participate, 346 completed eleven questions related to their experiences since March 2020. These questions covered topics such as access to personal protective equipment (PPE) and accurate information, communication with and support from government agencies, ability to find staff and new residents, ability to address pandemic-related concerns of residents’ families and staff, use of virtual visits and telehealth for residents, and visitor restrictions. Response categories ranged from 0 (strongly disagree) to 4 (strongly agree) and we coded “agree” and “strongly agree” responses as having experienced that issue. Among responding AL, 42% were located in rural or frontier areas. We present three findings. First, most AL experienced adverse impact due to COVID-19, especially regarding issues likely to be outside of their control compared to those within their control. Second, while almost all urban-based AL reported that their residents used virtual communication technologies and tools for telemedicine/telehealth (96%) or virtual social visits (96%), rural AL were less likely to report so (90% and 92%, respectively). Finally, rural AL experienced significantly greater staffing difficulties (75%) compared to their urban counterparts (82%). In sum, while all AL would benefit from better regulatory guidance on policies and access to PPE, rural AL might especially benefit from additional, context-specific resources.

Government Reform, Regulatory Change and Carbon Disclosure: Evidence from Australia

This paper examines the effect of two Australian environmental regulatory changes, specifically the Clean Energy Act (CEA) 2011 and the National Greenhouse and Energy Reporting (NGER) Act 2007 with reference to voluntary corporate carbon disclosure practices. In doing so, it describes the brief history of this carbon-related regulatory change, its scope, enforcement criteria and corporations’ disclosures. This is a longitudinal analysis of 219 annual reports of 73 listed corporations in Australia which were subjected to carbon tax and report carbon emissions as per the CEA 2011 and NGER Act 2007 accordingly. Any corporation or facility that emitted scope 1 emissions of 25,000 tonnes of carbon dioxide equivalent (CO2-e) or more were liable for a carbon tax in accordance with CEA 2011. Drawing on stakeholder theory and legitimacy theory, this study uses content analysis to examine corporate carbon disclosure. The findings suggest there is a considerable increase in the number of carbon-related disclosures following these regulations being enacted as law. In addition, carbon-specific communication has become much more prevalent and accounts for a larger proportion of the sampled organisations’ reported environmental information. The results of this study enrich the validity of the hypothesis that organisations would seek to legitimise their operations to stakeholders by increasing their environment-related declarations. The evidence presented in the analysis confirms the assertion that government environmental legislation/regulation has a positive impact on corporate behaviour and accountability. These findings have significant consequences for the government, decision-makers and the accounting profession, indicating that regulatory guidance enhances both mandatory and voluntary disclosure. It also offers key insights into the possible impacts of the carbon regulatory change for future research to consider.

Identification of Novel Modalities Through Bibliometric Analysis for Timely Development of Regulatory Guidance: A Case Study of T Cell Immunity

Background: The mission of medicines regulatory agencies is to ensure the timely access of innovative products for patients to improve public health. Thus, regulators should foresee evolving technologies and build expertise prior to reviewing innovative products. Novel modalities and new classes of therapeutics in biological or cell-based products represent a regulatory challenge because of knowledge gaps, as exemplified by the unexpected cytokine release syndrome in the first-in-human clinical trial of the CD28 super-agonist. Meanwhile, recent treatments harnessing T cell co-signaling pathways provide an opportunity for investigation. Therefore, this study aimed to systematically identify and evaluate novel modalities for T cell immunity to assess the need for regulatory guidance.Methods: A PubMed search was carried out using the query, “immun* AND t lymph*” to select publications. Subsequently, a citation network was created, followed by clustering and text mining to identify the modalities and classes of therapeutics under development.Results and Discussion: Analysis of the top 20 clusters revealed research domains characterized by keywords such as immune checkpoint antibody, chimeric antigen receptor (CAR)-T cells, microbiota, exosome, regulatory T cells, unconventional T cells, and vaccines. After reviewing the pharmacological concepts, clinical trial information, and available guidance, we presented a perspective on the future development of guidance for these domains.Conclusion: Bibliometric analyses identified a set of innovative modalities targeted for drug development with which regulatory guidance is going to catch up. This strategy could help in the successful development of upcoming modalities to ensure readiness for clinical application as part of horizon scanning.

Managing quality of cost information in clinical costing: evidence across seven countries

PurposeThe purpose is to assess the impact of clinical costing approaches on the quality of cost information in seven countries (Denmark, England, France, Germany, Ireland, the Netherlands and Portugal).Design/methodology/approachCosting practices in seven countries were analysed via questionnaires, interviews and relevant published material.FindingsAlthough clinical costing is intended to support a similar range of purposes, countries display considerable diversity in their approaches to costing in terms of the level of detail contained in regulatory guidance and the percentage of providers subject to such guidance for tariff setting. Guidance in all countries involves a mix of costing methods.Research limitations/implicationsThe authors propose a two-dimensional Materiality and Quality Score (2D MAQS) of costing systems that can support the complex trade-offs in managing the quality of cost information at both policy and provider level, and between financial and clinical concerns.Originality/valueThe authors explore the trade-offs between different dimensions of the quality (accuracy, decision relevance and standardization) and the cost of collecting and analysing cost information for disparate purposes.

Research on Business Environment Risk Governance Based on Occupational Claims: 1784 Cases of Food Safety Disputes

There are disputes on the legal acceptance of occupational claims and the risk of occupational claim spoiling business environment is skyrocketing. How to manage the risk of occupational claims in the business environment is the subject of urgent research, especially COVID-19 is ravaging the world and the risk of economic crisis is increasing dramatically. In this study, we collected 1784 cases of food occupational claims from the Chinese legal documents website. Using Excel, Review Manager 5.0 and SPSS 19.0, the number of cases prosecuted as “consumers” were obtained by means of textual analysis, and the development process was directly influenced by occupational claims, with 2017 as a great value point (watershed); the rate of losing occupational claim cases has been climbing since 2018; and the risk of losing occupational claims is higher than that of true meaningful consumer advocacy cases (Z = 6.99, p < 0.001), and in 2019, the risk of losing a case was 33.34 times higher than that of an ordinary consumer. The proportion of occupational claims in the total number of food safety disputes is positively correlated with official protective behavior; the failure rate of occupational claims is positively correlated with official regulatory behavior. The results show that occupational claims are being reexamined by society; the continued rise in the number of unsuccessful occupational claims cases indicates a lack of regulatory guidance for their profit-making behavior, the existence of malicious reporting complaints against business behavior, damage to the business environment, and a certain lack of legality. Therefore, it is proposed that laws and regulations should be in line with international standards, highlight the legal thinking and the concept of the rule of law, return to the original legislative intent, and build a five-in-one mechanism of “consumers, operators, media, government, and justice” to coordinate the management of occupational claims, crack down on occupational claims, and contribute to the creation of a good business environment.