Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials.

BACKGROUND: Engaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them. METHODS: Dyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes. RESULTS: The issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants. CONCLUSIONS: Ongoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

WHY IS THIS IMPORTANT?: Including the viewpoint of people living with chronic diseases when developing new therapeutics helps address their specific needs and improve their quality of life. This is very important for rare diseases, where individuals and their families face many challenges getting information, treatment, and support. WHAT DID WE DO?: Dyne Therapeutics, a company focused on developing potential medicines for rare muscle diseases, actively involved individuals living with Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) in their drug development process. Dyne organized workshops for individuals and families living with DMD and DM1 and participated in community advisory boards to gather input from patient advocacy organization leaders. HOW DID THIS HELP?: Partnering with individuals and families living with DMD and DM1 helped Dyne improve clinical trial design and reduce the difficulties affected individuals and their families face when participating in these trials. This valuable feedback has allowed Dyne to design clinical trials to better address the needs of those living with DMD and DM1.

Unmet Therapeutic Needs of Non-Ambulatory Patients with Duchenne Muscular Dystrophy: A Mixed-Method Analysis.

OBJECTIVE: Duchenne muscular dystrophy has been a launching pad for patient-focused drug development (PFDD). Yet, PFDD efforts have largely neglected non-ambulatory patients. To support PFDD efforts in this population, we primarily sought to understand the needs of non-ambulatory Duchenne patients and, secondarily, to examine these needs in the context of the PUL-PROM-a validated patient-reported outcome measure of upper limb functioning. METHODS: Non-ambulatory Duchenne patients or their caregivers from eight countries answered open-ended survey questions about patients' needs related to their most significant symptoms and important benefits of new treatments. The PUL-PROM was used to evaluate patients' upper limb functioning and was compared to data collected on non-ambulatory stage and quality of life. We thematically analyzed open-ended data, descriptively analyzed close-ended data, and compared themes by non-ambulatory stage. RESULTS: The study included 275 participants. Mean patient age was 24. Most patients were early-stage non-ambulatory (67%). Thematic analysis identified three congruent themes between significant symptoms and important benefits of new treatments: muscle functioning, especially upper limb function; body system functioning; and quality of life. Muscle functioning and body system functioning were endorsed more frequently in responses from early- and late-stage patients, respectively. Mean PUL-PROM total score was 22 with higher scores in early-stage patients (p ≤ 0.001). Upper limb function positively correlated with quality of life (r = 0.42, p ≤ 0.001). DISCUSSION: Non-ambulatory Duchenne patients want new treatments that improve upper limb functioning and body system functioning, and not exclusively regaining ambulation. The PUL-PROM can be used as a patient-centric measure that accounts for the needs of later-stage Duchenne patients.

A Comparison of Caregiver and Patient Preferences for Treating Duchenne Muscular Dystrophy.

BACKGROUND AND OBJECTIVES: Caregivers routinely inform medical and regulatory decision making in rare pediatric diseases. While differences in treatment preferences across caregivers and patients have been observed for Duchenne muscular dystrophy, this evidence was limited by small samples of patients and results were confounded by patient age and disease progression. We tested caregiver and patient preference concordance for treating Duchenne. METHODS: Preferences and demographic/clinical information from 115 caregivers and 107 patients were collected in an international study (response = 80%) using a previously developed discrete-choice experiment consisting of 12 experimentally controlled choice tasks. Each task presented two profiles that varied across four attributes: disease progression, drug failure probability, kidney damage risk, and fracture risk. Caregivers and patients were matched 1:1 based on patient age. We tested for concordance across each task and by comparing caregivers' and patients' maximum acceptable risk of drug failure, kidney damage, and fracture for a slowing of disease progression. RESULTS: The final analysis included 77 caregivers and 77 patients. No differences were observed in nationality (p = 0.969), disease stage (p = 0.180), or demographic/clinical factors (p = 0.093-0.857); however, patients were more optimistic (p = 0.030). Caregivers and patients chose similarly across tasks (p = 0.101-0.993). To slow disease progression by 1 year, caregivers and patients would tolerate a 9% and 11% increase in drug failure probability, respectively (p = 0.267). Alternatively, they would accept a 3% and 4% increase in the risk of kidney damage (p = 0.719) or a 15% and 20% increase in the risk of fracture (p = 0.534). CONCLUSIONS: Caregivers and patients had concordant preferences for treating Duchenne. Providers and regulators can trust both caregiver and patient report of preferences to inform medical decision making.

Helpful Lessons and Cautionary Tales: How Should COVID-19 Drug Development and Access Inform Approaches to Non-Pandemic Diseases?

After witnessing extraordinary scientific and regulatory efforts to speed development of and access to new COVID-19 interventions, patients facing other serious diseases have begun to ask "where's our Operation Warp Speed?" and "why isn't Emergency Use Authorization an option for our health crises?" Although this pandemic bears a number of unique features, the response to COVID-19 offers translatable lessons, in both its successes and failures, for non-pandemic diseases. These include the importance of collaborating across sectors, supporting the highest-priority research efforts, adopting rigorous and innovative trial designs, and sharing reliable information quickly. In addition, the regulatory response to the pandemic demonstrates that lowering standards for marketing authorization can result in increased safety concerns, missed opportunities for research and treatment, and delays in determining what works. Accordingly, policymakers and patient advocates seeking to build on the COVID-19 experience for non-pandemic diseases with unmet treatment needs should focus their efforts on promoting robust and efficient research designs, improving access to clinical trials, and facilitating use of the Food and Drug Administration's existing Expanded Access pathway.

Correction: Data Sharing Goals for Nonprofit Funders of Clinical Trials.

[This corrects the article DOI: 10.2196/23011.].

Data Sharing Goals for Nonprofit Funders of Clinical Trials.

Sharing clinical trial data can provide value to research participants and communities by accelerating the development of new knowledge and therapies as investigators merge data sets to conduct new analyses, reproduce published findings to raise standards for original research, and learn from the work of others to generate new research questions. Nonprofit funders, including disease advocacy and patient-focused organizations, play a pivotal role in the promotion and implementation of data sharing policies. Funders are uniquely positioned to promote and support a culture of data sharing by serving as trusted liaisons between potential research participants and investigators who wish to access these participants' networks for clinical trial recruitment. In short, nonprofit funders can drive policies and influence research culture. The purpose of this paper is to detail a set of aspirational goals and forward thinking, collaborative data sharing solutions for nonprofit funders to fold into existing funding policies. The goals of this paper convey the complexity of the opportunities and challenges facing nonprofit funders and the appropriate prioritization of data sharing within their organizations and may serve as a starting point for a data sharing toolkit for nonprofit funders of clinical trials to provide the clarity of mission and mechanisms to enforce the data sharing practices their communities already expect are happening.

Defining patient centricity with patients for patients and caregivers: a collaborative endeavour.

BACKGROUND: Patient engagement is an essential aspect in the research/development of biopharmaceutical products and disease management. Improving the lives of patients requires a deep understanding of their medical conditions, experiences, needs and priorities. However, a consistent definition of patient centricity is lacking. A series of initiatives was conducted to define patient centricity and its important principles impacting the biopharmaceutical industry. METHODS: Interviews, questionnaires and literature reviews were conducted involving key stakeholders to initially identify issues of importance to patients, healthcare providers and payers. Subsequently, two identical workshops which included 22 patients/carers created a definition of patient centricity and the healthcare values important to patients/caregivers. Outputs were tested in a validation exercise involving patients in predominantly US (n=470) and European (n=703) patient forums. RESULTS: Initial research provided deeper understanding of patient needs and key topics of interest that were used to cocreate a definition of patient centricity and 10 associated principles of importance to the biopharmaceutical industry. Wider testing of these outputs among predominantly US/European patient communities confirmed their validity. Patient centricity should be defined as 'Putting the patient first in an open and sustained engagement of the patient to respectfully and compassionately achieve the best experience and outcome for that person and their family'. Important principles for patients focused on education/information, cocreation, access and transparency. CONCLUSIONS: The development of a consistent definition of patient centricity and its associated principles provides an opportunity for biopharmaceutical companies to adopt and use these as a reference point for consistent patient engagement throughout the product life cycle.

Flow cytometric assessment of monocyte activation markers and circulating endothelial cells in patients with localized or metastatic breast cancer.

BACKGROUND: Monocyte activation in cancer patients may be reflective of anticancer activity. However, studies indicate that recruitment of macrophages can actually promote tumor growth and angiogenesis. Assessment of other microenvironmental cells such as circulating endothelial cells (CECs) may provide additional information regarding disease progression. The objective of this study was to assess monocyte activation and CECs in breast cancer patients and determine the potential clinical relevance during disease progression. METHODS: Patients (n = 41) with localized or metastatic breast cancer who were not currently receiving treatment were eligible for study inclusion. Peripheral blood was collected and analyzed by flow cytometry for monocyte activation (Leuko64 assay kit), and for CECs (CD146(+)CD45(-) phenotype). RESULTS: Metastatic breast cancer patients demonstrated a higher monocyte CD64 index relative to normal donors and localized breast cancer patients (P < 0.05). Furthermore, breast cancer patients had a lower monocyte CD163 index relative to normal donors (P = 0.008). Localized breast cancer patients demonstrated higher levels of CD146(+)CD45(-) cells CECs relative to metastatic breast cancer patients and normal donors. Within the localized breast cancer population, levels of CD146(+)CD45(-) cells increased with disease stage (P < 0.05). CONCLUSIONS: These results suggest that monocyte activation and CECs may play a role in breast cancer progression. We speculate that monocyte activation may reflect a reaction to metastatic cells and/or response to tissue damage caused by metastatic growth in distant organs. Furthermore, the observation that CECs increase with disease stage in localized breast cancer suggests that CECs could be a useful surrogate marker for disease progression in this patient population.