Families’ experiences with medical research for pediatric rare diseases : a qualitative ethnographic study of parents and children participating in clinical trials for Duchenne muscular dystrophy (DMD)

The biopharmaceutical industry has recently expanded its focus on developing new cures for rare diseases. As a growing number of personalised genomic treatments are tested in clinical trials, there is uncertainty about how to account for patient perspectives, and how to measure functional changes reported by patients and caregivers. The illness experiences of patients and families are also being reshaped as they adopt roles as collaborative stakeholders and participants in clinical studies. This dissertation examines these changes using data from qualitative ethnographic research conducted with families of children with Duchenne muscular dystrophy, a progressive and fatal genetic disease diagnosed in boys. Canadian and American families were followed using semi-structured interviews and observational methods as they participated in clinical trials testing a genomic treatment for DMD, called ataluren (formerly known as PTC124). Ethnographic work was also carried out with physicians, patient-advocates, and other professionals engaged in clinical neuromuscular research. The dissertation contributes to scholarly understanding of families’ everyday experiences in the clinical trial, the significance and meaning of investigational treatments from the patient perspective, and the social context in which pharmaceutical development for rare diseases occurs. I show how genetic research is reconfiguring patient communities and altering moral sensibilities about treatment and care, by revealing “lucky mutations” and new axes of biosocial commonality and difference. I explore the paths families take to the clinical trial, and the “stories of waiting” they tell about their experience in it. Finally, I examine how families navigate the uncertainty and liminality of their experience as trial subjects. I discuss how the trial unsettles taken-for-granted social roles, constraining clinical relationships and leaving parents to construct the significance of an experimental treatment in the context of limited information. In so doing, parents assemble and tell “narratives of efficacy” while administering study-drug to their children, drawing on their observations and those made by others. Though parents’ narratives are often dismissed as mere anecdote, I suggest they also offer insight for developing more personalised approaches to clinical research and outcome measurement for rare diseases, by restoring focus on the nuance, idiosyncrasy, and context of families’ experiences with investigational treatments.Arts, Faculty ofAnthropology, Department ofGraduat

The changing meaning of gene therapy : exploring the significance of curative genetic research in the narratives of families with Duchenne muscular dystrophy

Gene therapy and stem cell therapy are symbols of a futuristic age in biomedicine. These experimental treatments have led to speculation that many presently untreatable diseases will soon be cured. However, there has been relatively little study of how this conjecture affects families experiencing a serious genetic illness. This study is based on interviews conducted with ten families in which a child has Duchenne muscular dystrophy (DMD) - a lethal childhood disorder. Parents were asked to relate their hopes and expectations for advanced genetic research, and its relevance in their everyday lives. Building on a tradition of scholarship in the social sciences that examines how individuals make sense of their experiences with illness through narrative, I show how the field of gene therapy research is implicated in the process of emplotting and telling a story about DMD and remodifying it as circumstances change. I point to some of the ways in which the significance of curative genetic research for parents varies over time. I illustrate how the field of genetics serves as a narrative device, taking on different meanings depending on its place in the story parents tell about their child's disease. I also show how parents learn about genetic research mainly by participating in socially constituted communities of practice, a process I liken to the concept of legitimate peripheral participation. This study contributes to a growing debate about whether lay-actors are sufficiently informed vis-a-vis the risks and benefits involved in experimental medical research, by showing how studies of "therapeutic misconception" can overlook the broader picture. Attention is drawn to the manner in which research is situated in parents' personal biographies and everyday lives, to the socially constituted ways in which parents come to acquire knowledge about and construct expectations for the field of genetics, and to the multiple places that it occupies in the stories they construct and tell about their child's chronic illness. Brief overviews of the historical trajectory of gene therapy research, and recent developments in curative medical research related to DMD are also provided.Arts, Faculty ofAnthropology, Department ofGraduat

Continuity of care for children with complex chronic health conditions: parents' perspectives

Abstract Background Continuity of care has been explored largely from academic and service provider perspectives, and in relation to adult patient/client groups. We interviewed parents of children with complex chronic health conditions to examine how their experiences and perceptions of continuity of care fit with these perspectives; and to identify the salient factors in the experience of, and factors contributing to, continuity in this population. Methods Parents of 47 elementary school-aged children with spina bifida, Down syndrome, attention-deficit/hyperactivity disorder, Duchenne muscular dystrophy or cystic fibrosis participated in semi-structured interviews. Parents described and mapped the pattern of their interactions with service providers over time in all domains relevant to their child's health, well-being, and development (medical, rehabilitational, educational, and social supportive services), with particular attention paid to their perceptions of connectedness or coherency in these interactions. Verbatim transcripts were analyzed thematically using a framework approach to impose structure regarding parents' perspectives on continuity of care. Results Existing academic concepts of relational, informational and management continuity were all discernable in parents' narratives. A thorough knowledge of the child on the part of service providers emerged as extremely important to parents; such knowledge was underpinned by continuity of personal relationships, principally, and also by written information. For this population, notions of continuity extend to the full range of service providers these children and families need to achieve optimal health status, and are not limited to physicians and nurses. Communication among providers was seen as integral to perceived continuity. Compartmentalization of services and information led to parents assuming a necessary, though at times, uncomfortable, coordinating role. Geographic factors, institutional structures and practices, provider attitudes, and, on occasion, parent preferences and judgments, were all found to create barriers to "seamless" management and provision of care continuity across providers, settings, and sectors. Conclusions These findings add new perspectives to the understanding of continuity within chronically ill children's health care. They are relevant to contemporary initiatives to improve continuity of services to children with special health care needs, demonstrate the need for parental support of their important role in maintaining continuity, and suggest avenues for further research.</p

Continuity of care for children with complex chronic health conditions: parents' perspectives

Background: Continuity of care has been explored largely from academic and service provider perspectives, and in relation to adult patient/client groups. We interviewed parents of children with complex chronic health conditions to examine how their experiences and perceptions of continuity of care fit with these perspectives; and to identify the salient factors in the experience of, and factors contributing to, continuity in this population. Methods Parents of 47 elementary school-aged children with spina bifida, Down syndrome, attention-deficit/hyperactivity disorder, Duchenne muscular dystrophy or cystic fibrosis participated in semi-structured interviews. Parents described and mapped the pattern of their interactions with service providers over time in all domains relevant to their child's health, well-being, and development (medical, rehabilitational, educational, and social supportive services), with particular attention paid to their perceptions of connectedness or coherency in these interactions. Verbatim transcripts were analyzed thematically using a framework approach to impose structure regarding parents' perspectives on continuity of care. Results Existing academic concepts of relational, informational and management continuity were all discernable in parents' narratives. A thorough knowledge of the child on the part of service providers emerged as extremely important to parents; such knowledge was underpinned by continuity of personal relationships, principally, and also by written information. For this population, notions of continuity extend to the full range of service providers these children and families need to achieve optimal health status, and are not limited to physicians and nurses. Communication among providers was seen as integral to perceived continuity. Compartmentalization of services and information led to parents assuming a necessary, though at times, uncomfortable, coordinating role. Geographic factors, institutional structures and practices, provider attitudes, and, on occasion, parent preferences and judgments, were all found to create barriers to "seamless" management and provision of care continuity across providers, settings, and sectors. Conclusions These findings add new perspectives to the understanding of continuity within chronically ill children's health care. They are relevant to contemporary initiatives to improve continuity of services to children with special health care needs, demonstrate the need for parental support of their important role in maintaining continuity, and suggest avenues for further research.Anthropology, Department ofArts, Faculty ofPediatrics, Department ofPopulation and Public Health (SPPH), School ofNon UBCMedicine, Faculty ofReviewedFacult

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation