Opportunities and Challenges for Decentralized Clinical Trial Approaches: European Health Technology Assessment Perspective.

OBJECTIVES: Decentralized clinical trial (DCT) approaches are clinical trials in which some or all trial activities take place closer to participants' proximities instead of a traditional investigative site. Data from DCTs may be used for clinical and economic evaluations by health technology assessment (HTA) bodies to support reimbursement decision making. This study aimed to explore the opportunities and challenges for DCT approaches from an HTA perspective by interviewing representatives from European HTA bodies. METHODS: We conducted semistructured interviews with 25 European HTA representatives between September 2022 and February 2023, and transcripts were analyzed after thematic analysis. RESULTS: Two main themes were identified from the data relating to (1) DCT approaches in HTA and (2) trial-level acceptance and relevance. Experience with assessing DCTs was limited and a variety of knowledge about DCTs was observed. The respondents recognized the opportunity of DCTs to reduce recall bias when participant-reported outcome data can be collected more frequently and conveniently from home. Concerns were expressed about the data quality when participants become responsible for data collection. Despite this challenge, the respondents recognized the potential of DCTs to increase the generalizability of results because data can be collected in a setting reflective of the everyday situation potentially from a more diverse participant group. CONCLUSIONS: DCTs could generate relevant results for HTA decision making when data are collected in a real-world setting from a diverse participant group. Increased awareness of the opportunities and challenges could help HTA assessors in their appraisal of DCT approaches.

Direct-to-participant investigational medicinal product supply in clinical trials in Europe: Exploring the experiences of sponsors, site staff and couriers.

AIMS: Insights into the current practice of direct-to-participant (DtP) supply of investigational medicinal product (IMP) in the context of clinical trials conducted in Europe are needed, as regulations are unharmonized. This study is set out to explore how DtP IMP supply has been employed in Europe and what the advantages and disadvantages and barriers and facilitators of its implementation are. METHODS: We conducted semi-structured interviews with representatives from sponsor companies, courier services and site study staff involved in the IMP dispensing and delivery process in Europe. Interviews were conducted between May and November 2021, and data were analysed following thematic analysis. RESULTS: Sixteen respondents participated in one of the 12 interviews. Respondents had experience with different models of DtP IMP supply including shipment from the investigative site, a central pharmacy (a depot under the control of a pharmacist) and a local pharmacy-aiming to reduce trial participation burden. The respondents indicated that investigative site-to-participant shipment is not affected by regulatory barriers, but could burden site staff. Shipment from central locations was considered most efficient, but possible regulatory barriers related to maintaining participants' privacy and investigator oversight were identified. The respondents indicated that the involvement of local pharmacies to dispense IMP can be considered when the IMP is authorized. CONCLUSIONS: Several DtP IMP supply models are implemented in clinical trials conducted in Europe. In this study, three main DtP IMP models were identified, which can be referenced when describing these approaches for regulatory approval.

Guideline-recommended use of asthma medication by children is associated with parental information and knowledge: the PIAMA birth cohort.

PURPOSE: We investigated the use of asthma medication by children and the association of use as recommended by guidelines with modifiable risk factors: parental attitudes, knowledge of asthma medication and information provided by health care providers. METHODS: Questionnaire data were obtained from parents of 229 8-year-old children participating in the prevention and incidence of asthma and mite allergy birth cohort who used asthma medication in the past 12 months. They reported on their child's medication use, their own knowledge and attitudes towards the medication and their satisfaction with the information they received from health care providers. RESULTS: Irregular use of inhaled corticosteroids (ICS) was common: 40% of the parents only gave their child ICS when the child felt breathless and 52% only 'when the child needed it'; 15% of the parents tried to avoid giving medication, and about 25% of the parents sometimes discontinued medication. Parental knowledge of how asthma medication should be given was a major determinant of guideline-recommended use: Of the parents who knew that anti-inflammatory drugs should be taken everyday (53% of all parents), 84% reported that they actually gave their child the medicines everyday as compared with 25% of the parents who did not know this. Guideline-recommended use was also significantly associated with parental satisfaction with the amount of information received from health care providers. These associations were independent of maternal school education. CONCLUSIONS: Our findings suggest that substantial improvements in the use of asthma medication are feasible, and this could considerably improve the effectiveness of current asthma treatment.

Regulatory readiness to facilitate the appropriate use of innovation in clinical trials: The case of decentralized clinical trial approaches.

Methodological and operational clinical trial innovation is needed to address key challenges associated with clinical trials, including limited generalizability and (s)low recruitment rates. In this article, we discuss how appropriate implementation of innovative clinical trial approaches can be facilitated by a timely identification of, and response to, emerging situations and innovation by regulators (i.e. regulatory readiness) using decentralized clinical trial (DCT) approaches - in which trial activities are moved closer to participants and away from the investigative sites - as a case study example. Specifically, we discuss how explorative research (e.g. using regulatory sandboxes) can enable the collection of data on the usefulness of DCT approaches. Additionally, we argue that DCT approaches should be evaluated similarly to conventional clinical trials.

Validation of the GetReal Trial Tool - Facilitating discussion and understanding more pragmatic design choices and their implications.

BACKGROUND: The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while taking into account the risk of bias, precision, acceptability and operational feasibility. This study describes the validation of the GetReal Trial Tool. METHODS: Twelve experts took part in the GetReal Trial tool validation using the protocols of 6 trials conducted with pragmatic elements. The tool entails 7 domains with a total of 43 questions. A pooled Kappa statistic (95% CI) using random effects model was estimated using Open Meta (analyst) software. The possible operational challenges were collated and discussed with the trialists that conducted the trials. RESULTS: Agreement in the design choices made for the trial protocols was >50% for all the trials and all teams reached consensus during discussion. The pooled Kappa statistic (95% CI) was 0.236 (0.154-0.318). The GetReal Trial tool highlighted several operational challenges, of which almost half had been experienced previously by the trialists. Out of 25 additional operational challenges mentioned by the trialists, 76% were already highlighted by the tool. The tool was considered helpful to optimize trials right from the design stage. CONCLUSION: The GetReal Trial Tool helps to scrutinize the choice of study design in the light of Real World Evidence generation. The tool identifies most of the operational challenges experienced by trialists to date. The tool serves the intended purpose of facilitating discussion and understanding more pragmatic design choices and their implications.

Decentralised, patient-centric, site-less, virtual, and digital clinical trials? From confusion to consensus.

There is increasing interest in clinical trials that use technologies and other innovative operational approaches to organise trial activities around trial participants instead of investigator sites. A range of terms has been introduced to refer to this operational clinical trial model, including virtual, digital, remote, and decentralised clinical trials (DCTs). However, this lack of standardised terminology can cause confusion over what a particular trial model entails and for what purposes it can be used, hampering discussions by stakeholders on its acceptability and suitability. Here, we review the different terms described in the scientific literature, advocate the consistent use of a unified term, 'decentralised clinical trial,' and provide a detailed definition of this term.

Which decentralised trial activities are reported in clinical trial protocols of drug trials initiated in 2019-2020? A cross-sectional study in ClinicalTrials.gov.

OBJECTIVES: Decentralised clinical trial activities-such as participant recruitment via social media, data collection through wearables and direct-to-participant investigational medicinal product (IMP) supply-have the potential to change the way clinical trials (CTs) are conducted and with that to reduce the participation burden and improve generalisability. In this study, we investigated the decentralised and on-site conduct of trial activities as reported in CT protocols with a trial start date in 2019 or 2020. DESIGN: We ascertained the decentralised and on-site conduct for the following operational trial activities: participant outreach, prescreening, screening, obtaining informed consent, asynchronous communication, participant training, IMP supply, IMP adherence monitoring, CT monitoring, staff training and data collection. Results were compared for the public versus private sponsors, regions involved, trial phases and four time periods (the first and second half of 2019 and 2020, respectively). SETTING: Phases 2, 3 and 4 clinical drug trial protocols with a trial start date in 2019 or 2020 available from ClinicalTrials.gov. OUTCOME MEASURES: The occurrence of decentralised and on-site conduct of the predefined trial activities reported in CT protocols. RESULTS: For all trial activities, on-site conduct was more frequently reported than decentralised conduct. Decentralised conduct of the individual trial activities was reported in less than 25.6% of the 254 included protocols, except for decentralised data collection, which was reported in 68.9% of the protocols. More specifically, 81.9% of the phase 3 protocols reported decentralised data collection, compared with 73.3% and 47.0% of the phase 2 and 4 protocols, respectively. For several activities, including prescreening, screening and consenting, upward trends in reporting decentralised conduct were visible over time. CONCLUSIONS: Decentralised methods are used in CTs, mainly for data collection, but less frequently for other activities. Sharing best practices and a detailed description in protocols can drive the adoption of decentralised methods.

The GetReal Trial Tool: design, assess and discuss clinical drug trials in light of Real World Evidence generation.

Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake of these methods is slow for several reasons, including uncertainty about acceptability of trial results, lack of experience with the methodology and operational challenges. We developed the "GetReal Trial Tool," an easy-to-use online interface, which allows users to assess the impact of design choices on generalizability to routine clinical practice, while taking into account risk of bias, precision, acceptability and operational feasibility. The tool is grounded in the scientific literature combined with knowledge of experts from academia, pharmaceutical companies, HTA bodies, patient organizations, and regulators. The aim is to help researchers optimize trial design and facilitate translation of evidence from pragmatic trials to clinical practice. In this paper we describe the development, structure and application of the GetReal Trial Tool.

A cross-sectional survey on the early impact of COVID-19 on the uptake of decentralised trial methods in the conduct of clinical trials.

BACKGROUND: The COVID-19 pandemic significantly impacted the conduct of clinical trials through delay, interruption or cancellation. Decentralised methods in clinical trials could help to continue trials during a pandemic. This paper presents the results of an exploratory study conducted early in the pandemic to gain insight into and describe the experiences of organisations involved in clinical trials, with regard to the impact of COVID-19 on the conduct of trials, and the adoption of decentralised methods prior to, and as mitigation for the impact, of COVID-19. METHODS: A survey with 11 open-ended and four multiple choice questions was conducted in June 2020 among member organisations of the public-private "Trials@Home" consortium. The survey investigated (1) the impact and challenges of COVID-19 on the continuation of ongoing clinical trials, (2) the adoption of decentralised methods in clinical trials prior to and as a mitigation strategy for COVID-19, (3) the challenges of conducting clinical trials during COVID-19, (4) the expected permanency of COVID-19-driven changes to the adoption of decentralised methods in clinical trials, and (5) lessons learned from conducting clinical trials during the COVID-19 pandemic. A thematic, inductive analysis of open survey questions was performed, complemented with descriptive statistics (frequencies and distributions). RESULTS: The survey had a response rate of 81%. All organisations included in the analysis (n = 18) implemented (some) decentralised methods in their clinical trials prior to COVID-19, and 15 (83%) implemented decentralised methods as mitigation for COVID-19. Decentralised methods for IMP supply, patient-health care provider interaction and communication, clinic visits and source document verification were used more often as mitigation strategies than they were used prior to COVID-19. Many respondents expect to maintain those decentralised methods they implemented during COVID-19 in ongoing trials, as well as implement them in future trials. CONCLUSIONS: Decentralised methods are a widely implemented mitigation strategy for trial conduct in the face of the COVID-19 pandemic. The results of this survey show that there is an interest to continue the use of decentralised methods in future trials, but important points of attention have been identified that need solutions to help guide the transition from the traditional trial model to a more decentralised trial model.

Ethics review of decentralized clinical trials (DCTs): Results of a mock ethics review.

Decentralized clinical trials (DCTs) can be a valuable addition to the clinical trial landscape. However, the practice of DCTs is dependent on a regulatory system designed for conventional (site-based) trials. This study provides insight into the ethics review of DCTs. A 'mock ethics review' was performed in which members of European ethics committees (ECs) and national competent authorities (NCAs) discussed and reviewed a DCT protocol. Respondents expressed hesitancy toward DCTs and focused on potential risks and burdens. We advise to address these aspects explicitly when submitting a DCT protocol. We propose that both the benefits and risks of DCTs should be carefully monitored to advance the review and practice of this innovative approach to ethically optimize drug development.

Opportunities and Challenges for Decentralized Clinical Trials: European Regulators' Perspective.

Decentralized clinical trials (DCTs) have the potential to improve accessibility, diversity, and retention in clinical trials by moving trial activities to participants' homes and local surroundings. In this study, we conducted semi-structured interviews with 20 European regulators to identify regulatory challenges and opportunities for the implementation of DCTs in the European Union. The key opportunities for DCTs that were recognized by regulators include a reduced participation burden, which could facilitate the participation of underserved patients. In addition, regulators indicated that data collected in DCTs are expected to be more representative of the real world. Key challenges recognized by regulators for DCTs include concerns regarding investigator oversight and participants' safety when physical examinations and face-to-face contact are limited. To facilitate future learning, hybrid clinical trials with both on-site and decentralized elements are proposed by the respondents.

Asthma therapy during the first 8 years of life: a PIAMA cohort study.

OBJECTIVE: Many studies evaluated asthma medication use in children in a cross-sectional manner, yet little is known about longitudinal use patterns. This study describes the formation of a longitudinal data set on asthma medication use and shows first results regarding the prevalence and incidence of medication use. METHODS: The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) study is a prospective birth cohort study among 3963 Dutch children. Recruitment took place in 1996-1997. The data of the PIAMA birth cohort study were complemented with pharmacy data. Prescription information of family members was used to determine whether medication histories were complete from birth until age 8. The prevalence and incidence of asthma medication use was studied in children for whom complete medication histories were available. RESULTS: A first prescription for asthma medication was filled before age 8 by 280 (36%) children, with 88% starting therapy before age 5. Of all children who started therapy, 91.1% received short-acting beta(2)-agonists and 61.1% inhaled corticosteroids. CONCLUSION: The applied method of data collection rendered a data set including 777 children with complete medication histories for their first 8 years of life. This data set provides the opportunity to study longitudinal medication use patterns. First analyses show that asthma medication is initiated in a rather high percentage of children in this cohort and mainly at an age at which an asthma diagnosis cannot yet be firmly established.

Patterns of asthma medication use: early asthma therapy initiation and asthma outcomes at age 8.

Wheeze has many underlying pathophysiologies in childhood, but is the main reason for anti-asthma drugs prescription. This study was conducted to describe asthma medication use patterns among children in their first eight years of life. Longitudinal medication use data from 777 children participating in the PIAMA study were used. Medication patterns were described for four groups that started therapy before the third birthday, when the peak in prescriptions occurred in our cohort; short-acting ß-agonists (SABA), inhaled corticosteroids (ICS), SABA + ICS or none of these. One third (n = 255) of the children received a first SABA or ICS prescription before age 8. Only three children (1.2%) used medication continuously during follow-up. Of the children who started SABA, 53.8% discontinued within 1-2 years. Of the children who started ICS before age 3, 42.1% discontinued within 1-2 years and 31.6% received additional SABA. 41.5% of the children who started SABA + ICS used this short-term (≤1 -2 years) and 21.5% long-term (≥ 3 years). Fifteen percent of children who did not start asthma therapy in their first 3 years of life did receive prescriptions between age 3 and 8. Children prescribed SABA + ICS before age 3 had the highest prevalence of hyper responsiveness at age 8, and similar prevalence of atopy as the other groups. Asthma medication is prescribed frequently in the first 8 years of life, particularly before age 3, and only few children use it continuously. ICS and SABA prescription occurs especially in those who were more likely to develop signs of asthma at age 8.

What drives prescribing of asthma medication to children? A multilevel population-based study.

PURPOSE: Diagnosing asthma in children with asthmatic symptoms remains a challenge, particularly in preschool children. This challenge creates an opportunity for variability in prescribing. The aim of our study was to investigate how and to what degree patient, family, and physician characteristics influence prescribing of asthma medication in children. METHODS: We undertook a multilevel population-based study using the second Dutch national survey of general practice (DNSGP-2), 2001. Participants were 46,371 children aged 1 to 17 years belonging to 25,537 families registered with 109 general practitioners. Using a multilevel multivariate logistic regression analysis with 3 levels, our main outcome measure was the prescribing of asthma medication, defined as at least 1 prescription for beta(2)-adrenergic agonists, inhaled corticosteroids, cromones, or montelukast during the 1-year study period. RESULTS: We identified characteristics significantly associated with prescribing asthma medication on all 3 levels (child, family, and physician). The variance in prescribing among physicians was significantly higher with children who were younger than 6 years than with children aged 6 years and older (95% CI, 3.5%-25.2% vs 2.4%-13.4%). Several diagnoses other than asthma and asthmatic complaints were strongly associated with prescribing asthma medication, including bronchitis/bronchiolitis (OR = 9.04; 95% CI, 7.57-10.8) and cough (OR = 6.51; 95% CI, 5.68-7.47). CONCLUSIONS: Our study shows a much higher variance in prescribing patterns among general practitioners for children younger than 6 years compared with older children, which could be a direct result of the diagnostic complexities found in young children with asthmatic symptoms. Thus diagnostic gaps may lead to more physician-driven prescribing irrespective of the clinical context.

Prescription of respiratory medication without an asthma diagnosis in children: a population based study.

BACKGROUND: In pre-school children a diagnosis of asthma is not easily made and only a minority of wheezing children will develop persistent atopic asthma. According to the general consensus a diagnosis of asthma becomes more certain with increasing age. Therefore the congruence between asthma medication use and doctor-diagnosed asthma is expected to increase with age. The aim of this study is to evaluate the relationship between prescribing of asthma medication and doctor-diagnosed asthma in children age 0-17. METHODS: We studied all 74,580 children below 18 years of age, belonging to 95 GP practices within the second Dutch national survey of general practice (DNSGP-2), in which GPs registered all physician-patient contacts during the year 2001. Status on prescribing of asthma medication (at least one prescription for beta2-agonists, inhaled corticosteroids, cromones or montelukast) and doctor-diagnosed asthma (coded according to the International Classification of Primary Care) was determined. RESULTS: In total 7.5% of children received asthma medication and 4.1% had a diagnosis of asthma. Only 49% of all children receiving asthma medication was diagnosed as an asthmatic. Subgroup analyses on age, gender and therapy groups showed that the Positive Predictive Value (PPV) differs significantly between therapy groups only. The likelihood of having doctor-diagnosed asthma increased when a child received combination therapy of short acting beta2-agonists and inhaled corticosteroids (PPV = 0.64) and with the number of prescriptions (3 prescriptions or more, PPV = 0.66). Both prescribing of asthma medication and doctor-diagnosed asthma declined with age but the congruence between the two measures did not increase with age. CONCLUSION: In this study, less than half of all children receiving asthma medication had a registered diagnosis of asthma. Detailed subgroup analyses show that a diagnosis of asthma was present in at most 66%, even in groups of children treated intensively with asthma medication. Although age strongly influences the chance of being treated, remarkably, the congruence between prescribing of asthma medication and doctor-diagnosed asthma does not increase with age.

Women in Translational Medicine: Tools to Break the Glass Ceiling.

Despite the recent movements for female equality and empowerment, few women occupy top positions in scientific decision-making. The challenges women face during their career may arise from societal biases and the current scientific culture. We discuss the effect of such biases at three different levels of the career and provide suggestions to tackle them. At the societal level, gender roles can create a negative feedback loop in which women are discouraged from attaining top positions and men are discouraged from choosing a home-centred lifestyle. This loop can be broken early in life by providing children with female role models that have a work-centred life and opening up the discussion about gender roles at a young age. At the level of hiring, unconscious biases can lead to a preference for male candidates. The introduction of (unbiased) artificial intelligence algorithms and gender champions in the hiring process may restore the balance and give men and women an equal chance. At the level of coaching and evaluation, barriers that women face should be addressed on a personal level through the introduction of coaching and mentoring programmes. In addition, women may play a pivotal role in shifting the perception of scientific success away from bibliometric outcomes only towards a more diverse assessment of quality and societal relevance. Taken together, these suggestions may break the glass ceiling in the scientific world for women; create more gender diversity at the top and improve translational science in medicine.

Series: Pragmatic trials and real world evidence: Paper 1. Introduction.

This is the introductory paper in a series of eight papers. In this series, we integrate the theoretical design options with the practice of conducting pragmatic trials. For most new market-approved treatments, the clinical evidence is insufficient to fully guide physicians and policy makers in choosing the optimal treatment for their patients. Pragmatic trials can fill this gap, by providing evidence on the relative effectiveness of a treatment strategy in routine clinical practice, already in an early phase of development, while maintaining the strength of randomized controlled trials. Selecting the setting, study population, mode of intervention, comparator, and outcome are crucial in designing pragmatic trials. In combination with monitoring and data collection that does not change routine care, this will enable appropriate generalization to the target patient group in clinical practice. To benefit from the full potential of pragmatic trials, there is a need for guidance and tools in designing these studies while ensuring operational feasibility. This paper introduces the concept of pragmatic trial design. The complex interplay between pragmatic design options, feasibility, stakeholder acceptability, validity, precision, and generalizability will be clarified. In this way, balanced design choices can be made in pragmatic trials with an optimal chance of success in practice.

Series: Pragmatic trials and real world evidence: Paper 5. Usual care and real life comparators.

Pragmatic trials may deliver real-world evidence on the added value of new medications compared with usual care and inform decision making earlier in development. This fifth paper in a series on pragmatic trials in the Journal discusses usual care as a comparator and the allocation of treatment strategies. The allocation and implementation of treatment strategies should resemble clinical practice as closely as possible. Randomization at the level of the site, as opposed to at the individual level, may be preferred. Data analysis according to the intention-to-treat principle is recommended, and crossover between treatment arms and strong treatment preferences may be accounted for in the study design in specific situations. Although usual care is the comparator of choice, this may differ substantially between centers and countries complicating comparator choice. Using clinical guidelines to define usual care can be helpful in standardizing comparator treatments; however, this may decrease the applicability of the results to real-life settings. Conversely, using multiple usual-care treatment arms will increase the complexity of the study. The specific objectives of the trial and design choices should be discussed with all stakeholders to realize the full potential of the pragmatic trial.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent.

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs.

BACKGROUND: We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process. METHODS: We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets. RESULTS: We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results. CONCLUSIONS: We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.