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Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We hypothesized that overall disease activity or the severity of involvement of individual disease compartments, as measured by clinical and surrogate markers, predict the risk of avascular osteonecrosis (AVN) or fractures in type 1 Gaucher disease (GD1). We applied our risk-set matched case-control method to identify four patient groups within the International Collaborative Gaucher Group (ICGG) Gaucher Registry based on the presence and absence of AVN and fractures. Characteristics of GD1 were examined by comparing the distributions of each risk factor in cases versus matched controls using conditional logistic regression to calculate adjusted odds ratios (OR). Potential risk factors included hematological and visceral parameters, GD1 biomarkers, white blood cells, GBA1 genotype, and spine and femur dual-energy X-ray absorptiometry (DXA) Z-scores. In the total population of 5894 ICGG Gaucher Registry patients, 544 experienced at least one episode of AVN; 2008 reported no history of AVN. Clinical and surrogate markers of disease activity were similar in patients with and without AVN; patients with AVN were 1.6 times more likely to be anemic compared to matched controls (OR = 1.59; 95% confidence interval [CI], 1.06-2.38, p < 0.05). For fractures, 319 patients suffered fractures and 1233 had no prior history of fractures. Clinical and surrogate markers of disease in patients with and without fractures were similar, except for mean lumbar spine DXA Z-scores. Among patients with fractures, 49.3% had DXA Z-scores ≤ -1 compared to 31.0% in the control group. Compared to controls with Z-scores > -1.0, GD1 patients exhibiting Z-scores ≤ -1 had an OR of 5.55 (95% CI, 1.81-17.02, p < 0.01) for fracture. In GD1, after controlling for gender, year of birth, treatment status, and splenectomy status, we identified new risk factors for AVN and fractures. Concurrent anemia was associated with an increased risk for AVN. Low bone mineral density of the lumbar spine was a strong risk factor for fractures of the spine and femur in GD1., (Copyright © 2012 American Society for Bone and Mineral Research.)

Background: In clinical research of rare diseases, where small patient numbers and disease heterogeneity limit study design options, registries are a valuable resource for demographic and outcome information. However, in contrast to prospective, randomized clinical trials, the observational design of registries is prone to introduce selection bias and negatively impact the validity of data analyses. The objective of the study was to demonstrate the utility of case-control matching and the risk-set method in order to control bias in data from a rare disease registry. Data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were used as an example., Methods: A case-control matching analysis using the risk-set method was conducted to identify two groups of patients with type 1 Gaucher disease in the ICGG Gaucher Registry: patients with avascular osteonecrosis (AVN) and those without AVN. The frequency distributions of gender, decade of birth, treatment status, and splenectomy status were presented for cases and controls before and after matching. Odds ratios (and 95% confidence intervals) were calculated for each variable before and after matching., Results: The application of case-control matching methodology results in cohorts of cases (i.e., patients with AVN) and controls (i.e., patients without AVN) who have comparable distributions for four common parameters used in subject selection: gender, year of birth (age), treatment status, and splenectomy status. Matching resulted in odds ratios of approximately 1.00, indicating no bias., Conclusions: We demonstrated bias in case-control selection in subjects from a prototype rare disease registry and used case-control matching to minimize this bias. Therefore, this approach appears useful to study cohorts of heterogeneous patients in rare disease registries.

Objective: To describe demographic, genetic, and clinical characteristics of patients with neuronopathic Gaucher disease (NGD)., Methods: All patients enrolled in the Neurological Outcomes Subregistry of the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of June 2007 were identified., Results: The study cohort comprised 131 patients from 17 countries who were enrolled in the Neurological Outcomes Subregistry. The onset of neurological manifestations had occurred before 2 years of age in 47% (61 out of 131 patients), 2 years of age or older in 41% (54 out of 131), and could not be ascertained in the remaining 12% (16 out of 131). The most common manifestations were inability to look to the extreme up or down (45%, 55 out of 123), abnormally slow object tracking (43%, 53 out of 123), convergent squint (36%, 44 out of 121), and ataxia (15 to 20%, 18-27 out of 117). Seizures were reported in 19 out of 122 patients (16%), and myoclonic seizures were reported in 3 out of 121 patients (2%). The most common genotypes were L444P/L444P (76 out of 108, 70%), L444P/D409H (9 out of 108, 8%), D409H/D409H (8 out of 108, 7%), and L444P/rare allele (6 out of 108, 6%); full sequencing was not performed in all patients., Conclusions: Neurological manifestations of GD often begin to appear before the age of 2 years. The most common neurological signs and manifestations are brainstem abnormalities and fine motor dysfunction. The most common genotype is L444P/L444P.

Gaucher disease management in France is facilitated by CETG (Comitee of Evaluation and Treatment of Gaucher disease). Four hundred and fifty-six patients are enrolled in 2006 in the French Gaucher registry of CETG. Two hundred and thirty patients had treatment. Eighty five % are type 1, 10.5% type 2 and 5.5% type 3. Only 1 patient had a saposin C deficiency. Information on CETG is available on www.cetl.net.

Background: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy., Methods: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review., Results: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients., Conclusions: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

Background and Objectives: Since 1993 the demographic, clinical, analytical, genetic and follow-up data of Spanish patients with Gaucher's disease (GD) have been collected in an anonymous national database. Some statistical analyses of these data are reported concerning the distribution, clinical and genetic characteristics of GD in Spain and the response to enzyme replacement therapy (ERT) is evaluated., Design and Methods: We performed a cohort study in Spanish GD patients by national inquiry, submitted by mail to 75 Spanish hospitals (over 300 beds) directed to internal medicine, hematology and pediatric departments. The questionnaire included 30 questions (gender, height, weight, date of birth, date of diagnosis, abode and number of relatives affected, bone crises, neurologic symptoms, other symptoms, liver and spleen size, hemoglobin, leukocyte and platelet count, tartrate resistant acid phosphatase, ALT/AST, chitotrioxidase activity, total plasma cholesterol, triglycerides, high density lipoprotein cholesterol, enzymatic activity of acid -glycosides, mutation, X-ray examination, magnetic resonance imaging-MRI-evaluation, spleen removal, and orthopedic procedures (ERT, date of first infusion). Each case with a presumed diagnosis was considered an enrolled patient. Written informed consent was obtained from all patients. The cases without enzymatic or genetic diagnosis were studied in a reference laboratory (the same for all the samples). Clinical status was evaluated by Zimran's severity score index. The enzymatic activity of acid -glycosides was determined in cellular extracts of peripheral blood granulocytes by a fluorescent method using an artificial substrate (4-methyl-umbelliferyl -D-glycoside). Polymerase chain reaction (PCR) molecular analysis was performed in DNA samples to characterize the mutations (N370S, L444P, IVS2+1, 84GG, D409H, R463C and G377S) of the glycoside genes. Two groups were created according to age at diagnosis: children under 15 years and adults, in order to evaluate clinical, genetics and follow-up. Effectiveness of ERT was evaluated using objective parameters (hemoglobin, platelets, liver and spleen size, skeletal lesions), before and after therapy. In patients under ERT, quality of life (QOL) was assessed by a SF-36 modified inquiry, including 22 questions. Statistical analysis including descriptive and frequency distribution for each variable was performed, the ANOVA test was used to identify differences between groups. Paired t-tests (before and during therapy) were carried out. The degree of linear association among measured variables was estimated by Pearson's correlation., Results: By December 1999 one hundred and fifty-five patients from 117 families had been included from 66 Spanish Hospitals; the inquiry was complete for 114 patients. Mean age at diagnosis: 24.0+/-16.9 years, M/F: 72/83. No symptoms were present at diagnosis in 19.3%; visceral disease was present in 95.6% and bone disease in 62.4%. Hemoglobin levels, leukocyte and platelet counts were below the normal range in 62.3% of cases. Higher acid phosphatase levels were observed in 99% of cases; biochemical liver dysfunction tests were found in 42.9%. The test for acid glycosidase showed a marked decrease in enzymatic activity. Morphologic documentation (spleen or liver tissue, bone marrow biopsy or aspirate) of GD was obtained in 71% of the patients. The most frequent mutations observed were N370S (46.3% of the alleles detected), and L444P (18.5%). In 18.7% of the cases the disease was stable or progressing slightly; in 23.8% the spleen had been removed between 1-14 years after diagnosis and 60.6% were under ERT. Children showed both greater liver enlargement and higher SSI (p = 0.0001). There was a correlation between SSI and clinical or analytical data in adults patients for spleen size (Z: 3.142; CI: 0. 173-0.637; p= 0.0017). In 35 patients on ERT, clinical and analytic data improved as did self-evaluated QOL (p< 0.0001). (A