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Translating Rare-Disease Therapies Into Improved Care for Patients and Families

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Translating Rare-Disease Therapies Into Improved Care for Patients and Families © American College of Medical Genetics and Genomics REVIEW Open Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research? Beth K. Potter, PhD1,2, Sara D. Khangura, BA1, Kylie Tingley, BSc1, Pranesh Chakraborty MD, FRCPC2,3 and Julian Little, PhD1; in collaboration with the Canadian Inherited Metabolic Diseases Research Network There is a need for research to understand and improve health sys- hold the most promise for addressing priorities such as minimizing tems for rare diseases in order to ensure that new, efficacious thera- bias, accounting for cointerventions, identifying long-term impacts, pies developed through basic and early translational science lead to and considering clinical heterogeneity. To effectively engage with real benefits for patients. Such research must (i) focus on appropriate stakeholders, a knowledge exchange infrastructure is needed to foster­ patient-oriented outcomes, (ii) include robust study designs that can collaboration among patients with rare diseases and their families, accommodate real-world decision priorities, and (iii) involve effec- health-care providers, researchers, and policy decision makers. A key tive stakeholder-engagement strategies. For transformative therapies, priority for these groups must be collaboration toward a shared under- study outcomes will need to shift toward longer-term goals in rec- standing of the outcomes that are of most relevance to the facilitation ognition of success in preventing catastrophic outcomes. For incre- of patient-centered care. mental therapies, outcomes should be selected in recognition of the Genet Med advance online publication 9 April 2015 impact of care on quality of life for patients and families. To generate new evidence, we suggest that hybrid study designs integrating ele- Key Words: health-systems research; patient-oriented outcomes; ments of practice-based observational research and pragmatic trials practice-based research; rare diseases; translational research WHY HEALTH-SYSTEMS RESEARCH IS NEEDED translational medicine that there is a linear continuum from The fields of rare-disease research and clinical practice are rap- bench to bedside.8 Research to evaluate the implementation of idly changing. Technology such as lower-cost next-generation new therapies in real-world settings must respond to an evolv- sequencing has advanced our capacity to identify the genetic ing set of existing interventions and care pathways as well as basis for an increasing number of rare single-gene diseases.1 consider the roles of multiple decision makers, including This has led to substantial investment in diagnostic research,2 clinical providers and policy makers along with patients and which in turn provides a foundation for developing new treat- families. A nonlinear and multifaceted approach to develop- ments. By the year 2020, the goals of the International Rare ing, evaluating, implementing, and adapting an intervention as Diseases Research Consortium (IRDiRC) are to develop the part of a complete health-care system is described by the UK capacity to diagnose all rare diseases and to establish 200 new Medical Research Council in its guidance for developing and or repurposed rare-disease therapies.3 evaluating complex interventions.9 In addition to drawing from Realizing the full potential of new treatments will require that this guidance, the health-systems orientation that we argue is they be made available to patients within effective systems of needed fits within the paradigm of comparative-effectiveness care. The gap between treatment outcomes observed in highly research, which has an explicit applied purpose: to “assist con- controlled trials in selected patients and settings (i.e., treatment sumers, clinicians, purchasers, and policy makers to make efficacy) and actual impacts experienced by patients in com- informed decisions that will improve health care at both the mon clinical settings (i.e., treatment effectiveness)4,5 has led to individual and population levels.”10 a call for investment in research addressing the downstream Research focused on understanding and improving health translation of biomedical discoveries into improved popula- systems for patients with rare diseases must accompany the tion health;6,7 rare diseases are not exempt from this gap. The rapidly progressing basic and early translational science that is integration of new therapies for rare diseases into existing sys- currently leading to the development of promising new thera- tems of care, however, challenges an implicit assumption in pies. Herein, we describe priorities for such health-systems 1School of Epidemiology, Public Health, and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 2Newborn Screening Ontario, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 3Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Correspondence: Beth K. Potter ([email protected]) Submitted 13 August 2014; accepted 23 February 2015; advance online publication 9 April 2015. doi:10.1038/gim.2015.42 Genetics in medicine | Volume 18 | Number 2 | February 2016 117 REVIEW POTTER et al | Health-systems research for rare diseases research in the field of rare disease. We emphasize a need Table 1 Examples of “transformative” and “incremental” to identify the appropriate outcomes, study designs, and interventions for rare diseases stakeholder-engagement strategies to facilitate the successful Transformative Incremental implementation of new therapies toward improved care and ERT for hypophosphatasia23 ERT for mucopolysaccharidosis health for patients and their families. type II22 Ivacaftor for some patients with CF24 Airway clearance therapy OUTCOMES: DEFINING EFFECTIVENESS for CF33 While ideal interventions contribute to the triple aim of Biotin for biotinidase deficiency25 Hydroxycobalamin for improved medically defined outcomes, improved patient cobalamin C deficiency34a experiences and quality of life, and manageable health-system Diet therapy for PKU26 Sapropterin for some patients 11 impacts (including costs), trade-offs between these goals with PKU26 are usually necessary in a rare-disease context. For example, Nitisinone for tyrosinemia type I27 Long-term diet therapy for orphan drugs are often expensive for the health-care system galactosemia35a but may be highly valued by patients and families if they con- CF, cystic fibrosis; ERT, enzyme replacement therapy; PKU, phenylketonuria. 12 tribute to an improved quality of life. By contrast, severe aThese two examples (hydroxycobalamin for cobalamin C deficiency and long-term dietary restrictions or other lifestyle modifications may be diet therapy for galactosemia) are arguably more transformative/effective than the other examples in the right-hand column because both treatments can be lifesaving perceived as straightforward and inexpensive by health pro- early in infancy. However, these two interventions are less “transformative” than fessionals and policy makers but as highly burdensome by the examples in the left-hand column because outcomes remain quite poor for 13 a substantial proportion of individuals affected by cobalamin C deficiency and patients and their families. Researchers often rely on sur- galactosemia, respectively, despite treatment. This demonstrates that there is a rogate end points, including biomarkers that they perceive as continuum, rather than a dichotomy, between “transformative” and “incremental” meaningful, particularly if these end points have been corre- therapies. lated with clinical outcomes; however, surrogate end points are less convincing for both policy decision makers and patients.14 Defining effectiveness for transformative therapies Patient access to interventions, particularly expensive orphan The current momentum of biomedical research in rare disease drugs, often requires approval by multiple clinical and policy is expected to result in new interventions that will dramatically decision makers.15,16 Because these trade-offs are likely to be improve outcomes for patients for whom current treatment perceived differently by different stakeholders, disagreements options are limited. For such “transformative” interventions about whether a particular intervention is effective are com- (Table 1),23–27 barriers to initial implementation may be mini- mon.17 Such disagreements center on both the choice of out- mal. However, for many rare diseases, although transformative come and the level of improvement that constitutes a clinically treatments have led to important reductions in the risk of cata- meaningful change. strophic outcomes, previously unrecognized morbidities have As an example, among the most expensive drugs for rare dis- also been uncovered, and longer-term outcomes, while substan- eases are enzyme replacement therapies (ERTs) for lysosomal tially improved, have not been optimized.28,29 Reflecting the gap storage disorders.16 ERTs for six such disorders—Fabry dis- between efficacy and effectiveness in practice, such long-term ease, type I Gaucher disease, Pompe disease, and three types of outcomes are likely to depend on patient characteristics, coin- mucupolysaccharidoses (MPS; MPS I, MPS II, and MPS VI)— terventions, and models of service delivery that may affect have received regulatory approval in several jurisdictions.18,19 uptake and adherence. However, there is considerable
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