Theory-driven development of a medication adherence intervention delivered by eHealth and transplant team in allogeneic stem cell transplantation: the SMILe implementation science project

Medication adherence to immunosuppressants in allogeneic stem cell transplantation (alloSCT) is essential to achieve favorable clinical outcomes (e.g. control of Graft-versus-Host Disease). Over 600 apps supporting medication adherence exist, yet they lack successful implementation and sustainable use likely because of lack of end-user involvement and theoretical underpinnings in their development and insufficient attention to implementation methods to support their use in real-life settings. Medication adherence has three phases: initiation, implementation and persistence. We report the theory-driven development of an intervention module to support medication adherence (implementation and persistence phase) in alloSCT outpatients as a first step for future digitization and implementation in clinical setting within the SMILe project (Development, implementation and testing of an integrated care model in allogeneic SteM cell transplantatIon faciLitated by eHealth).; We applied Michie's Behavior Change Wheel (BCW) and the Capability-Opportunity-Motivation and Behavior (COM-B) model using three suggested stages followed by one stage added by our team regarding preparation for digitization of the intervention: (I) Defining the problem in behavioral terms; (II) Identifying intervention options; (III) Identifying content and implementation options; (IV) SMILe Care Model Prototype Development. Scientific evidence, data from a contextual analysis and patients'/caregivers' and clinical experts' inputs were compiled to work through these steps.; (I) Correct immunosuppressant taking and timing were defined as target behaviors. The intervention's focus was determined within the COM-B dimensions Capability (lack of knowledge, lack of routine), Opportunity (lack of cues, interruptions in daily routine) and Motivation (lack of problem solving, trivialization). (II) Five intervention functions were chosen, i.e. education, training, modelling, persuasion and enablement. (III) Twenty-four behavior change techniques were selected, e.g., goal setting, action planning and problem solving. (IV) Finally, seventeen user stories were developed to guide the SMILeApp's software development process.; Our example on the theory-driven development of an intervention module in alloSCT delivered by eHealth and transplant team using a rigorous 3 + 1-stage approach based on BCW, COM-B and agile software development techniques, can be used as methodological guidance for other eHealth intervention developers. Our approach has the potential to enhance successful implementation and sustained use of eHealth solutions in real-life settings

The SMILe integrated care model in allogeneic SteM cell TransplantatIon faciLitated by eHealth: a protocol for a hybrid effectiveness-implementation randomised controlled trial

While effectiveness outcomes of eHealth-facilitated integrated care models (eICMs) in transplant and oncological populations are promising, implementing and sustaining them in real-world settings remain challenging. Allogeneic stem cell transplant (alloSCT) patients could benefit from an eICM to enhance health outcomes. To combat health deterioration, integrating chronic illness management, including continuous symptom and health behaviour monitoring, can shorten reaction times. We will test the 1st-year post-alloSCT effectiveness and evaluate bundled implementation strategies to support the implementation of a newly developed and adapted eICM in allogeneic stem cell transplantation facilitated by eHealth (SMILe-ICM). SMILe-ICM has been designed by combining implementation, behavioural, and computer science methods. Adaptions were guided by FRAME and FRAME-IS. It consists of four modules: 1) monitoring & follow-up; 2) infection prevention; 3) physical activity; and 4) medication adherence, delivered via eHealth and a care coordinator (an Advanced Practice Nurse). The implementation was supported by contextually adapted implementation strategies (e.g., creating new clinical teams, informing local opinion leaders).; Using a hybrid effectiveness-implementation randomised controlled trial, we will include a consecutive sample of 80 adult alloSCT patients who were transplanted and followed by University Hospital Basel (Switzerland). Inclusion criteria are basic German proficiency; elementary computer literacy; internet access; and written informed consent. Patients will be excluded if their condition prevents the use of technology, or if they are followed up only at external centres. Patient-level (1:1) stratified randomisation into a usual care group and a SMILe-ICM group will take place 10 days pre-transplantation. To gauge the SMILe-ICM's effectiveness primary outcome (re-hospitalisation rate), secondary outcomes (healthcare utilization costs; length of inpatient re-hospitalizations, medication adherence; treatment and self-management burden; HRQoL; Graft-versus-Host Disease rate; survival; overall survival rate) and implementation outcomes (acceptability, appropriateness, feasibility, fidelity), we will use multi-method, multi-informant assessment (via questionnaires, interviews, electronic health record data, cost capture methods).; The SMILe-ICM has major innovative potential for reengineering alloSCT follow-up care, particularly regarding short- and medium-term outcomes. Our dual focus on implementation and effectiveness will both inform optimization of the SMILe-ICM and provide insights regarding implementation strategies and pathway, understudied in eHealth-facilitated ICMs in chronically ill populations.; ClinicalTrials.gov. Identifier: NCT04789863 . Registered April 01, 2021

Developing a medication adherence technologies repository: proposed structure and protocol for an online real-time Delphi study

Introduction An online interactive repository of available medication adherence technologies may facilitate their selection and adoption by different stakeholders. Developing a repository is among the main objectives of the European Network to Advance Best practices and technoLogy on medication adherencE (ENABLE) COST Action (CA19132). However, meeting the needs of diverse stakeholders requires careful consideration of the repository structure. Methods and analysis A real-time online Delphi study by stakeholders from 39 countries with research, practice, policy, patient representation and technology development backgrounds will be conducted. Eleven ENABLE members from 9 European countries formed an interdisciplinary steering committee to develop the repository structure, prepare study protocol and perform it. Definitions of medication adherence technologies and their attributes were developed iteratively through literature review, discussions within the steering committee and ENABLE Action members, following ontology development recommendations. Three domains (product and provider information (D1), medication adherence descriptors (D2) and evaluation and implementation (D3)) branching in 13 attribute groups are proposed: product and provider information, target use scenarios, target health conditions, medication regimen, medication adherence management components, monitoring/measurement methods and targets, intervention modes of delivery, target behaviour determinants, behaviour change techniques, intervention providers, intervention settings, quality indicators and implementation indicators. Stakeholders will evaluate the proposed definition and attributes’ relevance, clarity and completeness and have multiple opportunities to reconsider their evaluations based on aggregated feedback in real-time. Data collection will stop when the predetermined response rate will be achieved. We will quantify agreement and perform analyses of process indicators on the whole sample and per stakeholder group. Ethics and dissemination Ethical approval for the COST ENABLE activities was granted by the Malaga Regional Research Ethics Committee. The Delphi protocol was considered compliant regarding data protection and security by the Data Protection Officer from University of Basel. Findings from the Delphi study will form the basis for the ENABLE repository structure and related activities

Moving eHealth powered medication adherence interventions from trial to real world as part of the SMILe implementation science project

Medication adherence is suboptimal in many chronic condition populations. Medication adherence is the “process by which patients take their medications as prescribed” and consists of three phases: initiation (i.e., the first intake of a newly prescribed medication), implementation (i.e., following the prescribed daily regimen) and discontinuation (i.e., permanent cessation of the prescribed medication regimen). Non-adherence to the prescribed medication correlates strongly with declining chronic disease management, patient health status, quality of life and ability to work, combined with increases in health care costs and mortality rates. Because of the high prevalence and potential consequences of medication non-adherence, much research now focuses on improving methods of defining and measuring medication non-adherence, assessing its determinants, and developing effective multi-level interventions to reduce it. “The use of information and communication technologies in support of health and health-related fields,” i.e., eHealth, can support delivery of medication adherence interventions. eHealth itself is not a specific intervention, but rather a mode of delivery for educational, behavioral and psychosocial interventions. Evidence suggests positive effects of eHealth-delivered behavioral interventions on medication adherence, health and economic outcomes. However, for reasons attributed mainly to low quality and/or insufficient alignment between the proposed solution and the context, eHealth interventions are rarely sustained in daily clinical practice. Despite decades of research on the phenomenon of medication adherence and its effective management (i.e., assessment and support) in a number of chronically ill populations, comparatively little has focused on allogeneic stem cell transplantation (alloSCT) recipients. For example, although medication non-adherence has been found to be common in this population and is clearly associated with adverse outcomes, detailed information on adherence patterns and effective interventions is lacking. In addition, as in other chronically ill populations, alloSCT recipients commonly lack successful implementation and sustained use of medication adherence evidence in real-world settings, i.e., in daily clinical practice. This widespread failure to implement empirical evidence is an enormous waste of research resources. More importantly, though, it prevents patients from benefiting from effective interventions. The implementation of medication adherence evidence from research into real-world settings is complicated by research teams’ tendency to use self-developed (i.e., non-standard, untested) methods to support their implementation efforts. The process of translating medication adherence evidence into clinical practice calls for appropriate methods, such as those available from implementation science. As the "scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice," implementation science’s central focus is on bridging the gap between trials and real-world settings. Research teams who recognize the benefits of this focus can include implementation science principles in their projects from the earliest stages, then report their work in peer-reviewed journals to help others implement their evidence into clinical practice. This eight-chapter thesis has the overall aim of supporting the translation of eHealth powered medication adherence interventions from trial completion to real-world use. It is part of the Integrated Model of Care after Allogeneic SteM Cell TransplantatIon faciLitated by eHealth (SMILe) implementation science project, which aims to develop/adapt, implement and evaluate its integrated care model at the University Hospitals of Freiburg, Germany (UKF), and Basel, Switzerland (USB). Chapters 1 and 2 introduce its topic and describe its objectives. Chapters 3 to 6 present its scientific articles; Chapter 7 is a policy brief; and Chapter 8 is synthesis and discussion. Chapter 1 provides a general introduction to implementation science, medication adherence, eHealth and alloSCT. Chapter 2 describes the overall document’s aims. Chapter 3 describes a systematic review to assess the type and extent of information available in published solid organ transplantation and alloSCT medication adherence intervention randomized controlled trials (RCTs) to support real-world implementation of adherence-enhancing interventions. To facilitate the assessment processes, the adapted Peters’ criteria of implementation-relevant information were used (e.g., context, stakeholder involvement, implementation strategies, implementation outcomes reported). Twenty-three studies were included, all of which focused on the implementation phase of medication adherence. Even the most frequent criterion — feasibility study (43%) — was reported in fewer than half of the selected studies, while the two least frequent — implementation strategies (4%) and process evaluation (4%) — were reported in a single study each. The rarity of implementation-relevant information reported in medication adherence RCTs in transplant settings hinders the implementation of adherence-enhancing interventions in real-world transplant settings. Chapter 4 reports on the theory-driven development of an eHealth powered medication adherence module (implementation and persistence phase) as part of an integrated care model for alloSCT patients. The Behavior Change Wheel (BCW) both guided the development process and allowed its combination with implementation science and computer science principles. To work through the BCW's three steps, we employed findings from the SMILe study’s previously-conducted contextual analysis at the UKF, published evidence and input from stakeholders (i.e., patients, relatives, clinicians). After the third step, we added a fourth to develop the SMILe medication adherence module, including its digital component. To guide other researchers in developing eHealth powered behavior change interventions for other chronically ill populations and settings, this chapter provides a detailed description of this development process. Chapter 5 describes a qualitative study to explore alloSCT patients’ medication adherence- and self-management-related experiences and strategies, and to learn their perspectives and preferences regarding Electronic Monitoring (EM) devices. In three focus groups, participants discussed their post-alloSCT medication management-related challenges, e.g., frequent schedule changes. They also discussed how, to overcome these challenges, they developed strategies to bolster their adherence, such as linking their medication intake to other habits. During these focus groups, the participants additionally had the opportunity to test three EM systems, i.e., the Medication Event Monitoring System (MEMS) Cap®, Helping Hand® and Button® devices. As participants particularly appreciated the small size of the MEMS Button®, which made it possible to store it in or next to existing pillboxes, this EM device was selected for the SMILe hybrid effectiveness-implementation RCT at the USB. Chapter 6 reports on a systematic review conducted to provide an overview of published criteria for the description and evaluation of eHealth smartphone applications (apps). This was a first step towards developing a tool to systematize health care professionals’ assessment of eHealth apps for their patients. Overall, we identified 205 distinct criteria in 128 articles. No study included all criteria; and the labeling of criteria was inconsistent. To organize the criteria, based on the original dimensions reported in the included studies, we developed a conceptual framework for eHealth app evaluation. To fill potential gaps in the list, the research team conducted a consensus discussion. As a result, eleven new criteria were added, for a final total of 216. However, while this list is arguably comprehensive, it would be impractical for use in clinical practice. Therefore, our next step will be to use a Delphi consensus-building process to develop a much-shorter version of the instrument, as well as a user manual. In Chapter 7, we present a recently developed, future-oriented policy brief on priority setting to implement medication adherence interventions in Switzerland. In collaboration with stakeholders (i.e., researchers, health care professionals, patients, health care administrators and policy makers), we agreed on five priorities for creating a more enabling ecosystem for the development, implementation and sustainability of medication adherence interventions: raising public awareness, preparing a multilevel ecosystem, translation from research to real-world settings, strengthening the patient-as-partner paradigm and monitoring medication adherence. Working on these priorities will help bridge the gap between research and clinical practice and reduce the burden of medication non-adherence in Switzerland and beyond. Chapter 8 discusses how to move forward with medication adherence research in Switzerland and beyond. We position this dissertation’s work in relation to the priorities outlined by the policy brief described in Chapter 7, while also providing guidance to relevant stakeholders regarding possible next steps to strengthen medication adherence management at a national level. This thesis advances medication adherence in the alloSCT population and beyond. Methodologically, we provide a clear description of approaches that support the implementation of eHealth powered medication adherence evidence into real-world practice. With this as its goal, it begins by applying the adapted Peters’ criteria as a helpful, innovative method of evaluating implementation-relevant information in medication adherence RCTs in transplantation. Second, it provides clear guidance on the development of eHealth powered interventions that use state-of-the-art methodologies to support both behavior change and real-world implementation. The methods used here can also be adapted to other populations, behaviors and settings. Third, we provide guidance on how a specific measurement method, i.e., EM, can be selected for optimal application in real-world settings. Fourth, we propose a new conceptual framework for the evaluation of eHealth apps in clinical practice. And fifth, we provide an overarching policy framework that will guide future efforts to support and tackle medication non-adherence as a major public health policy issue in Switzerland and beyond. Content-wise, we highlight the enormous gap between the discovery of empirical evidence regarding medication adherence interventions in transplantation and the application of that evidence to real-world clinical practice. Further, we present the preferences of alloSCT patients regarding their use of an EM device, as well as the first medication adherence intervention to be delivered both by an alloSCT transplant team and by an eHealth app and implemented in real-world settings. Finally, we provide a comprehensive overview of eHealth app evaluation criteria published in the scientific literature. All of our methods can serve as guidance for other researchers. Based on our findings and recommendations, this thesis’ sharp focus on moving eHealth powered medication adherence interventions from the trial environment to real-world practice gives it the potential to achieve real impact in real-world settings

Medication adherence interventions in transplantation lack information on how to implement findings from randomized controlled trials in real-world settings: A systematic review

Growing numbers of randomized controlled trials (RCTs) are showing the effectiveness of interventions to improve medication adherence in transplantation recipients. However, real-world implementation is still a major challenge. This systematic review assesses the range of information available in RCTs supporting these interventions' clinical adoption in adult transplant populations.; We included RCTs of interventions that a) targeted any phase of medication adherence in solid organ or allogeneic stem cell transplantation recipients and b) were published between January 2015 and November 2020. We excluded study protocols, conference abstracts and studies focusing only on pediatric populations. We identified relevant database and trial registries as well as traced references backward and citations forward. Implementation-relevant information was evaluated using adapted versions of Peters' ten criteria: 1. healthcare/organizational context; 2. social/economic/policy context; 3. patient involvement; 4. other stakeholder involvement; 5. sample representativeness; 6. trial conducted in a real-world-setting; 7. presence of feasibility study; 8. implementation strategy; 9. process evaluation; 10. implementation outcomes, using a stoplight color-rating system.; Screening 17'004 titles/abstracts resulted in 23 eligible RCTs, including 2'339 patients (n = 19-209/study). All included studies focused on the implementation phase of medication adherence. The best-reported criteria were feasibility study (43%), representative sample (17%) and conducted in a real-world-setting (17%). Least reported were context (9%), implementation strategies (4%), process evaluation (4%).; RCTs testing medication adherence interventions tend to report limited implementation-relevant information. This hinders their translation to real-world transplant settings. Integrating implementation science principles early in the conceptualization of RCTs would fuel real-world-translation, reducing research waste

Exploring stem cell transplanted patients' perspectives on medication self-management and electronic moni-toring devices measuring medication adherence: A qualitative sub-study of the Swiss SMILe implementa-tion science project

Purpose: Little is known about allogeneic stem cell transplant (alloSCT) patients' medication adherence strategies. Acceptability and preferences regarding electronic monitoring (EM) systems to assess all three phases of medication adherence (ie, initiation, implementation, persistence) are crucial to allow their successful implementation in clinical or research settings but have not yet been evaluated. We therefore aimed to explore: 1) alloSCT patients' medication adherence and self-management strategies; and 2) their acceptability and preferences of three different EM systems ( MEMS Cap , Helping Hand, Button ) as part of the Swiss SMILe study . Patients and methods: Respecting anti-pandemic measures, we used a purposive sample of six adult alloSCT patients from the University Hospital Basel, Switzerland (USB)-6 weeks to 2 years post-alloSCT-to conduct three focus group sessions with two patients each. Using a semi-structured outline, we explored 1) patients' medication adherence strategies and medication self-management; and 2) their acceptance and preferences regarding EM use. The three tested EM systems were available for testing during each session. Discussions were audio-recorded, visualized using mind-mapping and analyzed using Mayring's qualitative content analysis. Results: Patients (33% females; mean age 54.6±16.3 years; 10.4±8.4 months post-alloSCT) used medication adherence enhancing strategies (eg, preparing pillbox, linking intake to a habit). Still, they indicated that post-alloSCT medication management was challenging (eg, frequent schedule changes). All participants preferred the MEMS Button . Participants said its small size and the possibility to combine it with existing pillboxes (eg, putting it into/next to them) made them more confident about implementing it in their daily lives. Conclusion: Regarding EM systems for medication adherence, end-user preferences and acceptability influence adoption and fidelity. Of the three systems tested, our sample found the MEMS Button most acceptable and most preferable. Therefore, we will use it for our USB SMILe study

Development of an integrated model of care for allogeneic stem cell transplantation facilitated by eHealth-the SMILe study

PURPOSE Allogeneic stem cell transplantation would benefit from re-engineering care towards an integrated eHealth-facilitated care model. With this paper we aim to: (1) describe the development of an integrated care model (ICM) in allogeneic SteM-cell-transplantatIon faciLitated by eHealth (SMILe) by combining implementation, behavioral, and computer science methods (e.g., contextual analysis, Behavior Change Wheel, and user-centered design combined with agile software development); and (2) describe that model's characteristics and its application in clinical practice. METHODS The SMILe intervention's development consisted of four steps, with implementation science methods informing each: (1) planning its set-up within a theoretical foundation; (2) using behavioral science methods to develop the content; (3) choosing and developing its delivery method (human/technology) using behavioral and computer science methods; and (4) describing its characteristics and application in clinical practice. RESULTS The SMILe intervention is embedded within the eHealth enhanced Chronic Care Model, entailing four self-management intervention modules, targeting monitoring and follow-up of important medical and symptom-related parameters, infection prevention, medication adherence, and physical activity. Interventions are delivered partly face-to-face by a care coordinator embedded within the transplant team, and partly via the SMILeApp that connects patients to the transplant team, who can monitor and rapidly respond to any relevant changes within 1 year post-transplant. CONCLUSION This paper provides stepwise guidance on how implementation, behavioral, and computer science methods can be used to develop interventions aiming to improve care for stem cell transplant patients in real-world clinical settings. This new care model is currently being tested in a hybrid I effectiveness-implementation trial

Context-specific adaptation of an eHealth-facilitated, integrated care model and tailoring its implementation strategies. A mixed-methods study as a part of the SMILe implementation science project

Background: Contextually adapting complex interventions and tailoring their implementation strategies is key to a successful and sustainable implementation. While reporting guidelines for adaptations and tailoring exist, less is known about how to conduct context-specific adaptations of complex health care interventions. Aims: To describe in methodological terms how the merging of contextual analysis results (step 1) with stakeholder involvement, and considering overarching regulations (step 2) informed our adaptation of an Integrated Care Model (ICM) for SteM cell transplantatIon faciLitated by eHealth (SMILe) and the tailoring of its implementation strategies (step 3). Methods: Step 1: We used a mixed-methods design at University Hospital Basel, guided by the Basel Approach for coNtextual ANAlysis (BANANA). Step 2: Adaptations of the SMILe-ICM and tailoring of implementation strategies were discussed with an interdisciplinary team (n = 28) by considering setting specific and higher-level regulatory scenarios. Usability tests were conducted with patients (n = 5) and clinicians (n = 4). Step 3: Adaptations were conducted by merging our results from steps 1 and 2 using the Framework for Reporting Adaptations and Modifications–Enhanced (FRAME). We tailored implementation strategies according to the Expert Recommendations for Implementing Change (ERIC) compilation. Results: Step 1: Current clinical practice was mostly acute-care-driven. Patients and clinicians valued eHealth-facilitated ICMs to support trustful patient-clinician relationships and the fitting of eHealth components to context-specific needs. Step 2: Based on information from project group meetings, adaptations were necessary on the organizational level (e.g., delivery of self-management information). Regulations informed the tailoring of SMILe-ICM`s visit timepoints and content; data protection management was adapted following Swiss regulations; and steering group meetings supported infrastructure access. The usability tests informed further adaptation of technology components. Step 3: Following FRAME and ERIC, SMILe-ICM and its implementation strategies were contextually adapted and tailored to setting-specific needs. Discussion: This study provides a context-driven methodological approach on how to conduct intervention adaptation including the tailoring of its implementation strategies. The revealed meso-, and macro-level differences of the contextual analysis suggest a more targeted approach to enable an in-depth adaptation process. A theory-guided adaptation phase is an important first step and should be sufficiently incorporated and budgeted in implementation science projects