The history and accomplishments of the ICGG Gaucher registry
Authors: Neal J. Weinreb, Paige Kaplan
Journal: American Journal of Hematology (2015)

The International Collaborative Gaucher Group (ICGG) Gaucher Registry (clinicaltrials.gov NCT00358943) is the largest ongoing, longitudinal, international database in the world that tracks the clinical, demographic, genetic, biochemical, and therapeutic characteristics of patients with Gaucher disease globally, irrespective of disease severity, treatment status, or treatment choice. Launched in 1991, the governance and scientific direction of the Registry is provided by an international group of physician experts in Gaucher disease with operational support from Genzyme, a Sanofi company (Cambridge, MA). Here we describe the history and some representative accomplishments of the ICGG Gaucher Registry. Gaucher disease, a rare (approximately 1:70,000 live births), autosomal recessive lysosomal storage disorder (LSD) is caused by deficient acid β-glucosidase (glucocerebrosidase) with accumulation of glucosylceramide (glucocerebroside) in tissue macrophages. Gaucher disease type 1, found in 90% of all patients with Gaucher disease worldwide, is differentiated from Gaucher disease type 2 and type 3 by the absence of early-onset neurological signs and symptoms. The clinical manifestations of the disease are variable and somewhat unpredictable. Patients may have a lengthy asymptomatic course with few signs of disease, or present at any age from childhood to late adulthood with combinations of thrombocytopenia, anemia, leukopenia, splenic and hepatic enlargement, skeletal disease (chronic bone pain, acute bone crises, defective bone mineralization, infarction, osteonecrosis, osteolysis, and pathological fractures), growth retardation, and decreased health-related quality of life 1. Until about 25 years ago, only non-specific palliative treatment (blood transfusion, splenectomy, orthopedic surgery) was available. The sole Gaucher disease registry was a 530-patient paper database compiled by Robert Lee 2. Despite a problem with selection bias favoring overtly symptomatic patients, the Lee Registry contributed important observations about risks of splenectomy and about concurrent malignancy in Gaucher disease type 1 patients and continues as a resource for follow-up of long-term outcomes and mortality analysis 3. In 1990, recognizing the rarity of Gaucher disease and the unmet needs of symptomatic patients, the U.S. Food and Drug Administration (FDA) approved mannose-terminated, human placental acid β-glucosidase intravenous infusion treatment for Gaucher disease (alglucerase, Ceredase®, Genzyme, a Sanofi company) based on a 12-patient, non-randomized, open-label clinical trial, but contingent on the manufacturer's commitment to comprehensive post-marketing reporting of response outcomes and adverse events. Going beyond minimal compliance standards, Genzyme subsequently initiated the ICGG Gaucher Registry, which has since grown from an initial enrollment of 16 U.S. patients in 1991 to more than 6,000 Gaucher disease type 1, type 2, and type 3 patients, regardless of treatment status, from 62 countries (54,000 patient-years of data) 4. For a rare disease such as Gaucher disease, a disease registry format was very suitable for meeting the objectives of the founding committee of Genzyme team members and independent Gaucher disease experts: to enhance the understanding of the variability, progression, and natural history of Gaucher disease; to help optimize care by providing recommendations for monitoring patients and reports on patient outcomes; and to evaluate the short-, intermediate- and long-term effectiveness of treatment. Unlike clinical trials or treatment registries that have restricted eligibility requirements, disease registries can collect clinical information in larger, more heterogeneous populations 5, 6. They are intended to collect observational longitudinal data from a "real world" setting, annotate phenotypes that define the natural history of chronic diseases in untreated patients, and provide context for evaluating therapeutic responses. Registries are useful for diseases affecting very small patient populations such as those with Gaucher disease (approximately 10,000 identified patients worldwide) and for analyzing sub-populations (e.g., children, pregnant women, patients with neuronopathic disease, or from a single country or region or with a specific genotype). With careful design and modern technology, registries can assure patient anonymity and confidentiality yet remain accessible for individual patient reports as well as queries and research projects. For more than 20 years, the ICGG Gaucher Registry has functioned as depicted above to increase scientific knowledge of Gaucher disease, to provide practical management guidance, and to positively impact patient care. With informed consent, all patients with Gaucher disease, regardless of treatment status or type of treatment, are eligible for inclusion. Registry benefits include generation of individual patient case reports (PCRs) that depict changes in the patient's condition and their current position relative to individualized treatment goals, assistance with data requests, queries and clinical questions, and inclusion at regional and national meetings. Participating physicians have full access to all their patient data and are encouraged to check and verify its accuracy. The Registry is supported logistically and financially by Genzyme Corporation (now Genzyme, a Sanofi company). However, governance and scientific direction are in the hands of a central board comprising international, Genzyme-independent physicians with peer-recognized expertise in Gaucher disease research and clinical management. Additional physicians serve on regional boards for North America, Europe, Latin America, and Asia-Pacific. Board members receive no compensation except for time spent attending two to four meetings each year. Since its inception, the Registry has received and processed hundreds of Gaucher disease-related questions covering diverse topics such as frequency of spine kyphosis ("humpback") and its relationship to splenectomy, age at which Gaucher disease was diagnosed in women, number of Gaucher disease patients with hepatitis and with liver cancer, number of children with Gaucher disease and kidney stones, and information about Gaucher disease patients with bone marrow or stem cell transplants. Many requests have dealt with better defining the effect of genotype on the clinical manifestations of disease. In addition, the Registry receives requests from numerous countries for what might be termed a collective treatment report card based on achievement of therapeutic goals. The volume of queries and report requests has posed a formidable challenge in prioritization and allocation of resources. The Registry has now been restructured with the aim of facilitating data access without compromise of patient confidentiality so that participating clinicians and investigators will be able to address their queries and generate some of their own reports directly. The database and Registry team continue to directly support a large number of presentations at regional, national, and international meetings and more than 30 peer-reviewed scientific papers have been published by members of the ICGG International and Regional Scientific Advisory Boards, often in collaboration with other investigators and medical personnel. Due to the large size of the Registry database, these publications have changed many earlier concepts and suppositions emanating from small cohort studies and cover a broad range of topics ranging from natural history of the disease to innovative statistical methodologies developed for the robust analysis of the Registry data (Table 1). The power of the Registry is qualified by several important limitations 7. Although the Registry contains information about treatment interruptions and discontinuations, it does not collect information related to treatment safety or treatment-associated adverse events. The enrolled population, although large and multinational, may not fully represent all Gaucher disease phenotypes. In populous developing and third-world countries, many potential patients with severe disease are yet to be identified and are therefore underrepresented. Significant numbers of undiagnosed individuals with asymptomatic disease (not necessarily restricted to the N370S/N370S genotype) may also be missing. Enrollment may be skewed towards patients followed at LSD centers of excellence with dedicated study coordinators, a bias potentially affecting not only outcome analysis but also completeness and accuracy of data entry. In some countries, enrollment and reporting are restricted or prohibited by regulation. Laboratory and imaging techniques are not standardized or subject to independent quality review and consistency in serial reports is not assured. There is some attrition of patients lost to follow-up and missing data that may not necessarily be random or recoverable. Although the Registry is not restricted to patients treated with imiglucerase, with the advent of alternative treatment options (miglustat, velaglucerase alfa, taliglucerase and the recently approved eliglustat) and the mandated creation of treatment-specific surveillance databases, new patient enrollment may be curtailed and data entry on patients who switch from one treatment to another may be terminated. Finally, the commercial sponsorship and oversight have raised theoretical, although never substantiated, concerns about analytical and publication bias. To address some of these issues, the Registry has evolved from the early days of paper case report forms and retrospective data checks to a state-of-the-art, interactive, web-based platform, Registry NXT, that promotes ease of data submission and real-time detection and correction of questionable entries (www.gaucherregistry.com). To increase transparency, participating investigators have exclusive and unrestricted access to their primary data which can be downloaded to spreadsheets for site-specific analyses and shared at their discretion (subject to health data privacy regulations) with other collaborating colleagues and patients. Registry NXT also allows direct patient access (via invitation by the treating physician) to individual case reports and other patient-oriented material, empowering patients to take the lead in asking questions, initiating conversations with their doctors, and participating in case management decisions. In addition, besides supporting a broad range of data requests, special emphasis is focused on hypothesis-driven data entry by research-committed participants and analysis of patient cohorts from sites with high-quality data. With effective firewalls and good-faith bargaining, Registry NXT might also offer a solution to fragmentation by commercial product. After more than 20 years, the ICGG Gaucher Registry is well-positioned to add to its past achievements. However, the outcome is contingent on continued strong leadership internally and externally; formulation of clinically important questions; plasticity in data collection; innovation in data analysis; adaptability to new patterns and standards of care; finding balance between necessary anonymity and fostering patient interest; linking up with activities of basic and translational scientists and integrating with bio-banks. The true measure of the ICGG Gaucher Registry will be its ongoing commitment to its original mission: to improve the quality of care and to significantly advance the medical and scientific understanding of Gaucher disease. The authors would especially like to recognize the participants in the initial organizational meeting of the ICGG Gaucher Registry: Norman Barton, Joel Charrow, Joan Esplin, Mary Anne Fitzpatrick, Paige Kaplan, Richard Moscicki, Gregory Pastores, Ron Scott, Neal Weinreb, Jeffrey Wisch, Don Yarson, the late John Gribble, and the late Rebecca Wappner. They also thank their colleagues on the ICGG Gaucher International and Regional boards as well as the patients with Gaucher disease worldwide and their physicians and health-care personnel who submit data to the IGCC Gaucher Registry and without whose support, none of this work would be possible. A final thanks to Pam Pickering of Conscience Creative and Cheryl Lathrop for editorial assistance, which was funded by Genzyme, a Sanofi company, and Laura Croal, PhD (medical communications manager for Gaucher disease, Genzyme Global Medical Affairs) for critical review of the manuscript. This article was supported by an unrestricted grant from Genzyme, a Sanofi company. The opinions expressed in this article are those of the authors and do not necessarily reflect those of Genzyme.