Clinical Trial Design Innovations for Precision Medicine in Asthma.

Severe asthma is a spectrum disorder with numerous subsets, many of which are defined by clinical history and a general predisposition for T2 inflammation. Most of the approved therapies for severe asthma have required clinical trial designs with population enrichment for exacerbation frequency and/or elevation of blood eosinophils. Moving beyond this framework will require trial designs that increase efficiency for studying nondominant subsets and continue to improve upon biomarker signatures. In addition to reviewing the current literature on biomarker-informed trials for severe asthma, this chapter will also review the advantages of master protocols and adaptive design methods for establishing the efficacy of new interventions in prospectively defined subsets of patients. The incorporation of methods that allow for data collection outside of traditional study visits at academic centers, called remote decentralized trial design, is a growing trend that may increase diversity in study participation and allow for enhanced resiliency during the COVID-19 pandemic. Finally, reaching the goals of precision medicine in asthma will require increased emphasis on effectiveness studies. Recent advances in real-world data utilization from electronic health records are also discussed with a view toward pragmatic trial designs that could also incorporate the evaluation of biomarker signatures.

Strategies to facilitate adolescent access to medicines: Improving regulatory guidance.

BACKGROUND: Historically, pediatric medicines are developed after adult trials are completed, even when identical drug targets and disease similarities exist across the populations. This has resulted in significant delays in the authorization of medicines for adolescent use, limiting access to beneficial drugs. This study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance documents as they set critical expectations for trial design and regulatory decision-making. METHODS: This study utilized a qualitative analysis approach. Guidance documents were identified via Food and Drug Administration and European Medicines Agency websites. Utilizing a blinded adjudication process, the documents were classified as permissive, exclusionary, or silent regarding recommendations about adolescent inclusion in adult clinical trials. A post hoc analysis of similarities and differences between the Food and Drug Administration and European Medicines Agency guidance documents was conducted to assess the possible role of regional pediatric research laws on age-inclusive trial methodologies as well as emergent themes by therapeutic area. RESULTS: In total, 96 Food and Drug Administration (1977 to 2019) and 106 European Medicines Agency (1987 to 2019) guidance documents were identified for analysis. The guidance contained explicit or implicit recommendations supporting adolescent inclusion in adult trials in 32% of Food and Drug Administration and 15% of European Medicines Agency documents, while 14% and 21%, respectively, were found to be exclusionary. A large number of guidance documents were silent regarding the applicability of adolescent-inclusive trial designs (53% and 64%, Food and Drug Administration and European Medicines Agency, respectively). Analysis by therapeutic area revealed the most permissive of adolescent inclusion in Food and Drug Administration guidance for infectious diseases and conditions requiring blood products in European Medicines Agency guidance. A more holistic approach to age-inclusive trial design was identified in disease guidance published by the Food and Drug Administration Oncology Center of Excellence. DISCUSSION: There are many influences on the development and/or revision of regulatory guidance documents. Substantial scientific knowledge and regulatory precedence for the inclusion of adolescents within adult trials are available to inform research approaches. Our study has identified important opportunities for the enhancement of guidance. For example, contextualization of developmental factors influencing adolescent disease progression provides insights into the role of adolescent inclusion. If addressed, guidance documents can facilitate broader acceptance of age-inclusive trial methodologies and accelerate adolescent access to medicines.

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

A qualitative study exploring caregivers' experiences, perspectives, and expectations for precision medicine in epilepsy in South Africa.

PURPOSE: Successful implementation of innovative Precision Medicine initiatives in the management of children with complex epilepsy is largely dependent on the caregivers' engagement with the technology as well as its accessibility and acceptability. We investigated the feasibility of implementing these initiatives in the South African setting by gathering information on the caregivers' experiences, perspectives, and expectations for Precision Management of Epilepsy (PME) initiatives. METHODS: We purposively recruited 12 participants from a cohort of 40 caregivers of children with complex epilepsy recruited for a PME study attending Red Cross War Memorial Children's Hospital (RCWMCH) in Cape Town, South Africa. Face-to-face semi-structured interviews were conducted using a pragmatic qualitative approach and themes were extracted using a thematic framework approach. RESULTS: All participants had ideas about the cause of epilepsy, but many did not think that epilepsy is a medical condition. There were several difficulties in adhering to medical treatment which was sometimes combined with traditional remedies and practices. Understanding of Precision Medicine in the context of research was limited and although participants were unclear about benefits, most were optimistic about the future. mHealth devices introduced new feelings and challenges for many participants. The four themes which emerged were: (1) Cause of epilepsy: uncertainty and conflicting views; (2) Need for healing; (3) PME mHealth devices; and (4) Feasibility of implementation of PME initiatives. CONCLUSION: For Precision Medicine to be widely accepted and beneficial, how people understand the cause of epilepsy, difficulties in adherence to treatment, and personal experiences need to be addressed.