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.

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.

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.

Overcoming ethical and legal obstacles to data linkage in health research: stakeholder perspectives.

Introduction: Data linkage for health research purposes enables the answering of countless new research questions, is said to be cost effective and less intrusive than other means of data collection. Nevertheless, health researchers are currently dealing with a complicated, fragmented, and inconsistent regulatory landscape with regard to the processing of data, and progress in health research is hindered. Aim: We designed a qualitative study to assess what different stakeholders perceive as ethical and legal obstacles to data linkage for health research purposes, and how these obstacles could be overcome. Methods: Two focus groups and eighteen semi-structured in-depth interviews were held to collect opinions and insights of various stakeholders. An inductive thematic analysis approach was used to identify overarching themes. Results: This study showed that the ambiguity regarding the 'correct' interpretation of the law, the fragmentation of policies governing the processing of personal health data, and the demandingness of legal requirements are experienced as causes for the impediment of data linkage for research purposes by the participating stakeholders. To remove or reduce these obstacles authoritative interpretations of the laws and regulations governing data linkage should be issued. The participants furthermore encouraged the harmonisation of data linkage policies, as well as promoting trust and transparency and the enhancement of technical and organisational measures. Lastly, there is a demand for legislative and regulatory modifications amongst the participants. Conclusions: To overcome the obstacles in data linkage for scientific research purposes, perhaps we should shift the focus from adapting the current laws and regulations governing data linkage, or even designing completely new laws, towards creating a more thorough understanding of the law and making better use of the flexibilities within the existing legislation. Important steps in achieving this shift could be clarification of the legal provisions governing data linkage by issuing authoritative interpretations, as well as the strengthening of ethical-legal oversight bodies.

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.

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.

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.

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.

COVID-19 and the Emerging Regulatory Guidance for Ongoing Clinical Trials in the European Union.

The coronavirus disease 2019 (COVID-19) pandemic and the accompanying control measures have significantly affected clinical trial (CT) conduct, and sponsors have needed to make rapid changes to their CT operations. As a result, regulatory guidance was pivotal during the initial phases of the pandemic. This study aimed to evaluate the regulatory readiness and guidance related to COVID-19 in the European Union (EU). The European Medicines Agency (EMA) and national competent authorities' (NCAs') websites were searched in September and October 2020 for guidances on the management of CTs during the pandemic published from January 2020 onward. "Regulatory readiness" was defined as the number of days from the first European COVID-19 case (January 24, 2020) to the first published guidance by the respective NCA. "Regulatory guidance" was evaluated by coding the guidances for the following predefined operational trial activities important for ongoing CTs: obtaining informed consent, participant information, clinic visits, home health visits, telemedicine visits, self-monitoring, investigational medicinal product (IMP) supply, IMP adherence monitoring, CT monitoring, documentation management, regulatory management, and safety management. Twenty-four of the 27 EU NCAs published country-specific guidance. The time from the first European COVID-19 case to the first published EMA guidance was 56 days and ranged from 47 to 66 days for the first national guidances. Guidance was provided most frequently for regulatory management (24/24), safety management (23/24), documentation management (22/24), and CT monitoring (22/24). The regulatory guidance provided during the pandemic, ensuring participant safety and data integrity, may now be the starting point to innovate future CT conduct.

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 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 8. Data collection and management.

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Furthermore, it should allow for the involvement of a representative sample of practices, physicians, and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data-collection systems and processes seems to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data, and the lack of a clear understanding of the data-collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extent existing health care databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach using a dedicated electronic case report form (eCRF). In this case, the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice.

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.

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.

The Social Value of Pragmatic Trials.

Pragmatic trials aim to directly inform health care decision-making through the collection of so-called 'real world data' from observations of comparative treatment effects in clinical practice. In order to ensure the applicability and feasibility of a pragmatic trial, design features may be necessary that deviate from standard research ethics requirements. Examples are traditional requirements to seek written informed consent and to perform extensive data and safety monitoring. Proposals for deviations from standard research ethics practice have resulted in controversy about their ethical acceptability. One of the justifications for altered procedures is the allegedly high social value of pragmatic trials. In order to properly operationalize the concept in the ethical assessment of pragmatic trial designs, specification is warranted. We identified three determinants from common claims about a pragmatic trial's social value: (1) the extent to which the research question has real world relevance, (2) the trial design's ability to generate a real world answer and (3) the probability of direct uptake of the results by decision-makers in practice. Subsequently, we discuss how these determinants should be applied to the practice of pragmatic trials, and to what extent they might be applicable to explanatory trials.

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.

Pragmatic trial design elements showed a different impact on trial interpretation and feasibility than explanatory elements.

OBJECTIVES: To illustrate how pragmatic trial design elements or inserting explanatory trial elements in pragmatic trials affect validity, generalizability, precision, and operational feasibility. STUDY DESIGN AND SETTING: From illustrative examples identified through the IMI Get Real Consortium, we selected randomized drug trials with a pragmatic design feature. We searched all publications on these trials for information on how pragmatic trial design features affect validity, generalizability, precision, or feasibility. RESULTS: We present examples from the Salford lung study, International Suicide Prevention Trial, Sequenced Treatment Alternatives to Relieve Depression, and Cluster Randomized Usual care vs. Caduet Investigation Assessing Long-term-risk trial. These examples show that incorporating pragmatic trial design elements in trials may affect generalizability, precision and validity and may lead to operational challenges different from traditional explanatory trials. Inserting explanatory trial elements into pragmatic trials may also affect validity, generalizability, and operational feasibility, especially when these trial elements are incorporated in one arm of the trial only. Design choices that positively affect one of these domains (e.g., generalizability) may negatively affect others (e.g., feasibility). CONCLUSION: Consequences of incorporating pragmatic or explanatory trial design elements in pragmatic trials should be explicitly considered and balanced for all relevant domains, including validity, generalizability, precision, and operational feasibility. Tools are needed to make these consequences more transparent.