Sharing is caring: a call for a new era of rare disease research and development.

Scientific advances in the understanding of the genetics and mechanisms of many rare diseases with previously unknown etiologies are inspiring optimism in the patient, clinical, and research communities and there is hope that disease-specific treatments are on the way. However, the rare disease community has reached a critical point in which its increasingly fragmented structure and operating models are threatening its ability to harness the full potential of advancing genomic and computational technologies. Changes are therefore needed to overcome these issues plaguing many rare diseases while also supporting economically viable therapy development. In "Data silos are undermining drug development and failing rare disease patients (Orphanet Journal of Rare Disease, Apr 2021)," we outlined many of the broad issues underpinning the increasingly fragmented and siloed nature of the rare disease space, as well as how the issues encountered by this community are representative of biomedical research more generally. Here, we propose several initiatives for key stakeholders - including regulators, private and public foundations, and research institutions - to reorient the rare disease ecosystem and its incentives in a way that we believe would cultivate and accelerate innovation. Specifically, we propose supporting non-proprietary patient registries, greater data standardization, global regulatory harmonization, and new business models that encourage data sharing and research collaboration as the default mode. Leadership needs to be integrated across sectors to drive meaningful change between patients, industry, sponsors, and academic medical centers. To transform the research and development landscape and unlock its vast healthcare, economic, and scientific potential for rare disease patients, a new model is ultimately the goal for all.

Coefficient of Fat Absorption to Measure the Efficacy of Pancreatic Enzyme Replacement Therapy in People With Cystic Fibrosis: Gold Standard or Coal Standard?

OBJECTIVES: We sought data on the validity, reliability, responsiveness, and feasibility of the coefficient of fat absorption (CFA) as a measure of pancreatic enzyme replacement therapy (PERT) efficacy in people with cystic fibrosis (pwCF) and reviewed the literature for alternative measures. METHODS: We searched PubMed for the Medical Subject Heading cystic fibrosis and the key words cystic fibrosis, fat absorption, CFA, and fecal fat imbalance; historical articles; and citations in bibliographies. RESULTS: The lower the CFA, the greater its variability; thus, it is less variable in healthy individuals who have higher CFA than pwCF. In addition, the test-retest values for CFA are more variable in pwCF than the general population. There is no correlation between CFA and body mass index or PERT dose but CFA is related to gastrointestinal signs and symptoms. Research-quality CFA studies are expensive, time consuming, and odious to pwCF and research staff. Sparse stool tests, breath tests, and blood tests of fat absorption have been studied as potential alternatives to CFA to measure PERT efficacy. CONCLUSIONS: Based on the evidence, we conclude that CFA as a measure of the efficacy of PERT is more of a "coal standard" than a gold standard; developing suitable alternatives should be a priority.

FABry Disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI): A new Fabry disease-specific gastrointestinal outcomes instrument.

PURPOSE: Fabry disease is a rare multisystemic disorder caused by functional deficiency of the lysosomal enzyme alpha-galactosidase A. Gastrointestinal (GI) signs and symptoms are among the earliest clinical manifestations in patients with Fabry disease but are often nonspecific, misdiagnosed, and untreated. No instruments have been developed specifically to assess GI signs and symptoms in Fabry disease. The FABry disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI) was developed to address this unmet need and is intended for use in clinical trials (24-h FABPRO-GI) and real-world settings (7-day FABPRO-GI). METHODS: Findings from a literature review, expert advisory meetings, and patient concept elicitation interviews (CEIs) were summarized into conceptual models. These conceptual models were used to develop preliminary versions of the 24-h and 7-day FABPRO-GI. Cognitive debriefing interviews (CDIs) were conducted with additional patients to assess content validity, including understandability, relevance, and comprehensiveness of the preliminary versions of the 24-h and 7-day FABPRO-GI. RESULTS: Literature review (n = 17 articles), expert advisory meetings (n = 5), and patient CEIs (n = 17) identified mostly overlapping Fabry disease-related GI signs and symptoms, including abdominal cramps, bloating, and diarrhea, and informed development of the preliminary 24-h and 7-day FABPRO-GI. CDIs (n = 15) provided evidence of content validity and informed revisions of the 24-h and 7-day FABPRO-GI. CONCLUSION: With evidence of content validity, the 24-h and 7-day FABPRO-GI are the first Fabry disease-specific patient-reported outcomes to assess GI signs and symptoms in patients with Fabry disease with potential for use in clinical trials and real-world settings, respectively.

Data silos are undermining drug development and failing rare disease patients.

Data silos are proliferating while research and development activity explode following genetic and immunological advances for many clinically described disorders with previously unknown etiologies. The latter event has inspired optimism in the patient, clinical, and research communities that disease-specific treatments are on the way. However, we fear the tendency of various stakeholders to balkanize databases in proprietary formats, driven by current economic and academic incentives, will inevitably fragment the expanding knowledge base and undermine current and future research efforts to develop much-needed treatments. The proliferation of proprietary databases, compounded by a paucity of meaningful outcome measures and/or good natural history data, slows our ability to generate scalable solutions to benefit chronically underserved patient populations in ways that would translate to more common diseases. The current research and development landscape sets too many projects up for unnecessary failure, particularly in the rare disease sphere, and does a grave disservice to highly vulnerable patients. This system also encourages the collection of redundant data in uncoordinated parallel studies and registries to ultimately delay or deny potential treatments for ostensibly tractable diseases; it also promotes the waste of precious time, energy, and resources. Groups at the National Institutes of Health and Food and Drug Administration have started programs to address these issues. However, we and many others feel there should be significantly more discussion of how to coordinate and scale registry efforts. Such discourse aims to reduce needless complexity and duplication of efforts, as well as promote a pre-competitive knowledge ecosystem for rare disease drug development that cultivates and accelerates innovation.

Use of the patient-reported outcomes measurement information system (PROMIS®) to assess late-onset Pompe disease severity.

BACKGROUND: Patient-Reported Outcomes provide an opportunity for patients to establish dialogue with pharmaceutical or biotechnology companies about their health conditions without interpretation by a clinician or anyone else. However, Patient-Reported Outcomes that can be widely applicable for use in patient-focused drug development or clinical trial designs are not yet validated for all diseases. The aim of this study report was to provide supportive evidence of the construct and content validity of selected Patient-Reported Outcomes Measurement Information System (PROMIS®) questionnaires compared with other disease-relevant clinical outcome measures, including the 6-Minute Walk Distance, forced vital capacity, and Manual Muscle Test, in late-onset Pompe disease and to provide supportive evidence that the selected PROMIS measures are relevant and important to these patients. METHODS: Thirty patients with late-onset Pompe disease completed five PROMIS questionnaires that were chosen based on patient and provider feedback, along with discussion with key opinion leaders who are experts in Pompe disease. The Amicus Pompe Patient Advisory Board also provided patient experience feedback using the PROMIS questionnaires. Clinical outcome measures (6-Minute Walk Distance, forced vital capacity, and Manual Muscle Test) were collected at the Duke University Pompe Disease Clinical Research Program during a single visit. RESULTS: The Patient Advisory Board rated the questionnaires as representative of an unmet need. Correlation data demonstrated moderate to strong correlations of PROMIS questionnaires with the specified clinical outcome measures (6-Minute Walk Distance, forced vital capacity, and Manual Muscle Test). These data supported the construct and content validity of the PROMIS questionnaires because they confirmed the motor signs and symptoms of functional disability observed in patients with Pompe disease. CONCLUSIONS: The correlations indicate that the clinical outcome measures assess important concepts related to patient-reported experiences. The Patient Advisory Board findings suggest that the selected PROMIS questionnaires are meaningful and address important concepts to patients with Pompe disease. The data were collected from a small number of patients at a single time point; further studies are needed with additional PROMIS questionnaires, which should include measures of motor function and health-related quality of life, in a larger number of patients followed up longitudinally.

Extrapolation of Adult Efficacy to Pediatric Patients With Chemotherapy-Induced Nausea and Vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common treatment-related adverse event that negatively impacts the quality of life of cancer patients. During pediatric drug development, extrapolation of efficacy from adult to pediatric populations is a pathway that can minimize the exposure of children to unnecessary clinical trials, improve efficiency, and increase the likelihood of success in obtaining a pediatric indication. The acceptability of the use of extrapolation depends on a series of evidence-based assumptions regarding the similarity of disease, response to intervention, and exposure-response relationships between adult and pediatric patients. This study evaluated publicly available summaries of data submitted to the US Food and Drug Administration for drugs approved for CINV to assess the feasibility of extrapolation for future development programs. Extracted data included trial design, emetogenic potential of chemotherapy, primary end points, participant enrollment criteria, and antiemetic pharmacokinetics. Adult and pediatric clinical trial designs for assessment of efficacy and safety shared key design elements. Antiemetic drugs found to be efficacious in adults were also efficacious in pediatric patients. Systemic drug concentrations at approved doses were similar for ondansetron, granisetron, and aprepitant, but an exposure-response analysis of palonosetron in children suggested that higher palonosetron systemic exposure is necessary for the prevention of CINV in the pediatric population. For 5-hydroxytryptamine-3 and neurokinin-1 receptor antagonist antiemetic drugs, efficacy in adults predicts efficacy in children, supporting the extrapolation of effectiveness of an antiemetic product in children from adequate and well-controlled studies in adult patients with CINV.

Global Harmonization of Pediatric Drug Development: Critical for Progress for Developing Safe and Effective Therapeutic Agents for Children.

The article, "Questionable Industry-Sponsored Studies in Children and Adolescents in Slovenia" provides an opportunity to discuss evolving US and EU legislative measures to improve the available clinical trial-derived pediatric data and provide coherent labeling for pediatric providers in dosing of drugs for children.

Comparison of the EMA and FDA Guidelines on Ulcerative Colitis Drug Development.

BACKGROUND & AIMS: In 2016, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) released revised EMA and new FDA draft guidelines related to the development of drugs intended for the treatment of ulcerative colitis. We sought to compare and contrast the EMA draft guideline with the FDA draft guidance to facilitate further discussion and perhaps harmonization between the 2 guidelines when they are finalized. METHODS: A concordance document was created by arranging like or similar topics addressed by the guidelines side by side in a tabular format. This concordance table served as a source for writing the narrative. The first draft was subjected to repeated rounds of reviews and revisions by the authors and outside reviewers, all of them familiar with the subject matter from a regulatory science and/or academic perspective. RESULTS: The FDA guidance focuses on end points, whereas the EMA guideline additionally supplies much useful information for trial design. FDA guidance appears more aspirational, suggesting the development of entirely new patient-reported outcome instruments and the incorporation of a not-yet-validated histology instrument into the definition of mucosal healing. CONCLUSIONS: The guidelines by the FDA and the EMA complement each other and together are aimed to further practical drug development toward more clinically relevant end points in ulcerative colitis. Efforts are needed to harmonize the documents.

Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders.

Rare or orphan diseases often are inherited and overwhelmingly affect children. Many of these diseases have no treatments, are incurable, and have a devastating impact on patients and their families. Regulatory standards for drug approval for rare diseases must ensure that patients receive safe and efficacious treatments. However, regulatory bodies have shown flexibility in applying these standards to drug development in rare diseases, given the unique challenges that hinder efficient and effective traditional clinical trials, including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints.To take steps toward improving rare disease clinical development strategies under current global regulatory statutes, Amicus Therapeutics, Inc. and BioNJ convened a 1-day meeting that included representatives from the Food and Drug Administration (FDA), biopharmaceutical industry, and not-for-profit agencies. The meeting focused on orphan diseases in pediatric and adult patients and was intended to identify potential strategies to overcome regulatory hurdles through open collaboration.During this meeting, several strategies were identified to minimize the limitations associated with low patient numbers in rare diseases, including the use of natural history to generate historical control data in comparisons, simulations, and identifying inclusion/exclusion criteria and appropriate endpoints. Novel approaches to clinical trial design were discussed to minimize patient exposure to placebo and to reduce the numbers of patients and clinical trials needed for providing substantial evidence. Novel statistical analysis approaches were also discussed to address the inherent challenges of small patient numbers. Areas of urgent unmet need were identified, including the need to develop registries that protect patient identities, to establish close collaboration and communication between the sponsor and regulatory bodies to address methodological and statistical challenges, to collaborate in pre-competitive opportunities within multiple sponsors and in conjunction with academia and disease-specific patient advocacy groups for optimal data sharing, and to develop harmonized guidelines for data extrapolation from source to target pediatric populations. Ultimately, these innovations will help in solving many regulatory challenges in rare disease drug development and encourage the availability of new treatments for patients with rare diseases.

Pediatric Inflammatory Bowel Disease Clinical Innovations Meeting of the Crohn's & Colitis Foundation: Charting the Future of Pediatric IBD.

The Crohn's & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure.10.1093/ibd/izy205_video1izy205.video15799266615001.

Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial.

BACKGROUND: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. METHODS: We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301). RESULTS: After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). CONCLUSIONS: Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease. TRIAL REGISTRATION: NCT00925301 ; June 19, 2009.

Pediatric Intestinal Failure-Associated Liver Disease: Challenges in Identifying Clinically Relevant Biomarkers.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) is complex and diagnosed by concurrent use of parenteral nutrition, clinical presentation, and alterations in hepatic biomarkers exclusive of other causes of liver disease. In comparison with individual measures, composite biomarkers may provide a more effective means for assessing disease progression and response to treatment than single parameters. Since IFALD is considered by some to be a type of drug-induced liver injury (DILI), those diagnostic criteria could potentially be used in this population. Using a preexisting database of children treated for IFALD, our aim was to determine if a similar composite biomarker could be applied to this population. STUDY DESIGN: Adult DILI criteria were applied at baseline, when treatment for IFALD (ie, direct bilirubin ≥2.0 mg/dL) was initiated. RESULTS: A total of 214 patients with IFALD treated at Boston Children's Hospital were identified; 168 patients were eligible for analysis. Most patients analyzed were male (61%) and preterm (87%). Alkaline phosphatase (ALP) ≥2× upper limit of normal (ULN) captured the least amount of DILI (11%), while γ-glutamyltransferase (GGT) ≥1× ULN accounted for the most (62%). Using adult DILI criteria, 60 (39%) patients with IFALD were found to have DILI. Substituting GGT ≥1× ULN for ALP ≥2× ULN improved the sensitivity, with 105 (69%) of patients meeting at least 1 criterion for DILI. CONCLUSION: Numerous challenges made it difficult to apply the DILI criteria to children with IFALD. Direct bilirubin, fractionated ALP, and perhaps GGT may be more suitable. Given its complex etiology and the age-based differences due to hepatic immaturity and growth, a more suitable composite marker needs to be developed to assess IFALD in this population.

Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response.

OBJECTIVES: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. METHODS: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. RESULTS: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching Cmax values with adults. CONCLUSIONS: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure-response for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.

Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration.

OBJECTIVE: There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization of current thinking about clinical outcome assessments (COAs) and biomarkers to facilitate drug development in pediatric CD. METHODS: Scientists from the United States Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan had monthly teleconferences from January 2014 through May 2015. A literature review was conducted to assess the measurement properties of all existing COA tools and to evaluate the current landscape of biomarkers used in pediatric CD. Based on the findings of literature review, we reached the consensus on the strategic approaches for evaluating outcomes in pediatric CD trials. RESULTS: The pediatric Crohn's Disease Activity Index, Crohn's Disease Activity Index, and Harvey-Bradshaw's index were used in pediatric CD clinical studies. But they lack adequate measurement properties (validity, reliability, and ability to detect change of the treatment) that are required to support approval of products intended to treat pediatric CD. Biomarkers (ie, fecal lactoferrin, osteoprotegerin, and calprotectin) have shown some promise for their potential as noninvasive surrogate endpoints in CD. CONCLUSIONS: Lack of well-defined and reliable COAs presents a hurdle for global drug development in pediatric CD. It is essential to develop well-defined and reliable COAs that can measure meaningful clinical benefit for patients in terms of how they feel, function, and survive. Development of noninvasive biomarkers as reliable surrogate endpoints needs to be further explored.

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base.

In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.