Kylie Tingley

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

There is a need for research to understand and improve health systems for rare diseases in order to ensure that new, efficacious therapies developed through basic and early translational science lead to real benefits for patients. Such research must (i) focus on appropriate patient-oriented outcomes, (ii) include robust study designs that can accommodate real-world decision priorities, and (iii) involve effective stakeholder-engagement strategies. For transformative therapies, study outcomes will need to shift toward longer-term goals in recognition of success in preventing catastrophic outcomes. For incremental therapies, outcomes should be selected in recognition of the impact of care on quality of life for patients and families. To generate new evidence, we suggest that hybrid study designs integrating elements of practice-based observational research and pragmatic trials hold the most promise for addressing priorities such as minimizing bias, accounting for cointerventions, identifying long-term impacts, and considering clinical heterogeneity. To effectively engage with stakeholders, a knowledge exchange infrastructure is needed to foster collaboration among patients with rare diseases and their families, health-care providers, researchers, and policy decision makers. A key priority for these groups must be collaboration toward a shared understanding of the outcomes that are of most relevance to the facilitation of patient-centered care.Genet Med 18 2, 117–123.

Child and family experiences with inborn errors of metabolism: a qualitative interview study with representatives of patient groups

BackgroundPatient-centered health care for children with inborn errors of metabolism (IEM) and their families is important and requires an understanding of patient experiences, needs, and priorities. IEM-specific patient groups have emerged as important voices within these rare disease communities and are uniquely positioned to contribute to this understanding. We conducted qualitative interviews with IEM patient group representatives to increase understanding of patient and family experiences, needs, and priorities and inform patient-centered research and care.MethodsWe developed a sampling frame of patient groups representing IEM disease communities from Canada, the United States, and United Kingdom. With consent, we interviewed participants to explore their views on experiences, needs, and outcomes that are most important to children with IEM and their families. We analyzed the data using a qualitative descriptive approach to identify key themes and sub-themes.ResultsWe interviewed 18 organizational representatives between February 28 and September 17, 2014, representing 16 IEMs and/or disease categories. Twelve participants voluntarily self-identified as parents and/or were themselves patients. Three key themes emerged from the coded data: managing the uncertainty associated with raising and caring for a child with a rare disease; challenges associated with the affected child’s life transitions, and; the collective struggle for improved outcomes and interventions that rare disease communities navigate.ConclusionHealth care providers can support children with IEM and their families by acknowledging and reducing uncertainty, supporting families through children’s life transitions, and contributing to rare disease communities’ progress toward improved interventions, experiences, and outcomes.

Scoping review of patient- and family-oriented outcomes and measures for chronic pediatric disease

BackgroundImprovements in health care for children with chronic diseases must be informed by research that emphasizes outcomes of importance to patients and families. To support a program of research in the field of rare inborn errors of metabolism (IEM), we conducted a broad scoping review of primary studies that: (i) focused on chronic pediatric diseases similar to IEM in etiology or manifestations and in complexity of management; (ii) reported patient- and/or family-oriented outcomes; and (iii) measured these outcomes using self-administered tools.MethodsWe developed a comprehensive review protocol and implemented an electronic search strategy to identify relevant citations in Medline, EMBASE, DARE and Cochrane. Two reviewers applied pre-specified criteria to titles/abstracts using a liberal accelerated approach. Articles eligible for full-text review were screened by two independent reviewers with discrepancies resolved by consensus. One researcher abstracted data on study characteristics, patient- and family-oriented outcomes, and self-administered measures. Data were validated by a second researcher.Results4,118 citations were screened with 304 articles included. Across all included reports, the most-represented diseases were diabetes (35%), cerebral palsy (23%) and epilepsy (18%). We identified 43 unique patient- and family-oriented outcomes from among five emergent domains, with mental health outcomes appearing most frequently. The studies reported the use of 405 independent self-administered measures of these outcomes.ConclusionsPatient- and family-oriented research investigating chronic pediatric diseases emphasizes mental health and appears to be relatively well-developed in the diabetes literature. Future research can build on this foundation while identifying additional outcomes that are priorities for patients and families.

Reimbursement-based economics - What is it and how can we use it to inform drug policy reform?

In Ontario, approximately

Using a meta-narrative literature review and focus groups with key stakeholders to identify perceived challenges and solutions for generating robust evidence on the effectiveness of treatments for rare diseases

3.8 billion is spent annually on publicly funded drug programs. The annual growth in Ontario Public Drug Program (OPDP) expenditure has been limited to 1.2% over the course of 3 years. Concurrently, the Ontario Drug Policy Research Network (ODPRN) was appointed to conduct drug class review research relating to formulary modernization within the OPDP. Drug class reviews by ODPRN incorporate a novel methodological technique called reimbursement‐based economics, which focuses on reimbursement strategies and may be particularly relevant for policy‐makers.

Establishing core outcome sets for phenylketonuria (PKU) and medium-chain Acyl-CoA dehydrogenase (MCAD) deficiency in children: study protocol for systematic reviews and Delphi surveys

IntroductionFor many rare diseases, strong analytic study designs for evaluating the efficacy and effectiveness of interventions are challenging to implement because of small, geographically dispersed patient populations and underlying clinical heterogeneity. The objective of this study was to integrate perspectives from published literature and key rare disease stakeholders to better understand the perceived challenges and proposed methodological approaches to research on clinical interventions for rare diseases.MethodsWe used a meta-narrative literature review and focus group interviews with key rare disease stakeholders to better understand the perceived challenges in generating and synthesizing treatment effectiveness evidence, and to describe various research methods for mitigating these identified challenges. Data from both components of this study were synthesized narratively according to research paradigms that emerged from our data.ResultsResults from our meta-narrative literature review and focus group interviews revealed three fundamental challenges in generating robust treatment effectiveness evidence for rare diseases: i) limitations in recruiting a sufficient sample size to achieve planned statistical power; ii) inability to account for clinical heterogeneity and assess treatment effects across a clinical spectrum; and iii) reliance on short-term, surrogate outcomes whose clinical relevance is often unclear. We mapped these challenges and associated solutions to three interrelated research paradigms: i) explanatory evidence generation; ii) comparative effectiveness/pragmatic evidence generation; and iii) patient-oriented evidence generation. Within each research paradigm, numerous criticisms and potential solutions have been described with respect to overcoming these challenges from a research study design perspective.ConclusionsOver time, discussions about clinical research for interventions for rare diseases have moved beyond methodological approaches to overcome challenges related to explanatory evidence generation, with increased recognition of the importance of pragmatic and patient-oriented evidence. Future directions for our work include developing a framework to expand current evidence synthesis practices to take into consideration many of the concepts discussed in this paper.

Metabolic Clinic Atlas: Organization of Care for Children with Inherited Metabolic Disease in Canada

BackgroundInherited metabolic diseases (IMD) are a large group of rare single-gene disorders that are typically diagnosed early in life. There are important evidence gaps related to the comparative effectiveness of therapies for IMD, which are in part due to challenges in conducting randomized controlled trials (RCTs) for rare diseases. Registry-based RCTs present a unique opportunity to address these challenges provided the registries implement standardized collection of outcomes that are important to patients and their caregivers and to clinical providers and healthcare systems. Currently there is no core outcome set (COS) for studies evaluating interventions for paediatric IMD. This protocol outlines a study that will establish COS for each of two relatively common IMD in children, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.MethodsThis two-part study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Part 1 includes a rapid review and development of an evidence map to identify a comprehensive listing of outcomes reported in past studies of PKU and MCAD deficiency. The review follows established methods for knowledge synthesis, including a comprehensive search strategy, two stages of screening citations against inclusion/exclusion criteria by two reviewers working independently, and extraction of important data elements from eligible studies, including details of the outcomes collected and outcome measurement instruments. The review findings will inform part 2 of our study, a set of Delphi surveys to establish consensus on the highest priority outcomes for each condition. Healthcare providers, families of children with PKU or MCAD deficiency, and health system decision-makers will be invited to participate in two to three rounds of Delphi surveys. The design of the surveys will involve parents of children with IMD who are part of a family advisory forum.DiscussionThis protocol is a crucial step in developing the capacity to launch RCTs with meaningful outcomes that address comparative effectiveness questions in the field of paediatric IMD. Such trials will contribute high-quality evidence to inform decision-making by patients and their family members, clinicians, and policy-makers.

Experiences of caregivers of children with inherited metabolic diseases: a qualitative study

INTRODUCTION Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the countrys Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. METHODS Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. RESULTS We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. CONCLUSIONS The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.