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Gliklich RE, Dreyer NA, Leavy MB, editors. Registries for Evaluating Patient Outcomes: A User's Guide [Internet]. 3rd edition. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Apr.

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Registries for Evaluating Patient Outcomes: A User's Guide [Internet]. 3rd edition.

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20Rare Disease Registries

1. Introduction

There is no single, unifying definition of a rare disease. Rare diseases are defined, from a regulatory and policy perspective, as any condition or disease affecting fewer than 200,000 individuals in the United States, or alternatively, determined to be of low prevalence (fewer than 5 individuals per 10,000) in the European Union.1, 2 In the United States, the Orphan Drug Act (P.L. 97-414) was adopted in 1983 in an effort to encourage activities by industry (and to a lesser extent other funding and research bodies) through tax incentives, market exclusivity, user fee exemptions and other incentives to target development of therapies for rare diseases. This legislation, as well as other regulations and similar international initiatives, resulted in a marked increase in rare disease research funding and development efforts for related drugs and biologics. Success of these compounds in coming to market, however, has been hampered by an incomplete understanding of the underlying disease mechanisms and relevant clinical endpoints, as well as limitations associated with identifying a large enough sample of comparable patients for clinical trials.

The scarcity of relevant knowledge and experience with most rare diseases creates a unique need for cooperation and infrastructure. Support is needed for research initiatives that aim to better understand the distribution and determinants of these diseases and to develop new therapies and other interventions. Innovations in genetics, molecular and computational biology, and other technological advances in basic research are rapidly evolving; however, translating this progress into clinic research and securing governmental or private funding in early stages remains challenging. Some of these challenges can be addressed efficiently through a systematic collection of clinical, genetic, and biologic data in the form of longitudinal patient registries and other coordinated data sources.

The use of observational data methods, including prospective long-term patient registries, is a critical tool in building a broad and comprehensive knowledge base for these often heterogeneous diseases. Important data include the prevalence and distribution of these diseases and key patient, familial, and disease characteristics, including the natural history of the disease. Although many of the basic concepts around registry planning, design, and implementation are directly applicable these disease registries, rare diseases pose some unique challenges. The range of stakeholders for rare diseases is inherently different, which has a direct effect on implementation, governance, funding, communication and as well as their level of interest and willingness to participate in the study of rare diseases. Clinicians with relevant expertise and direct exposure to managing these patients are limited necessitating a broad outreach to identify and recruit enough patients to understand the epidemiology and natural history of the disease. In addition, because of knowledge gaps, the scope and objectives of rare disease registries are often broader than in a typical disease registry. The absence of standards of care or treatment guidelines in many cases, the common use of experimental and adjunctive therapies, and the incomplete understanding of how these conditions should be monitored in the absence of established or widely accessible biomarkers provide opportunities for rare disease registries to set the agenda for disease research. Since amassing a sizable population from which any patterns of rare diseases can be discerned is more difficult, novel approaches are often required to both define rare diseases and their relevant outcomes (in other words, scientifically validated and accepted criteria may not exist). Lastly, patient advocacy and support groups are smaller for these often less well-known diseases and may play different roles than in a more traditional disease registry.

This chapter provides an overview of the development of patient registries for rare diseases and the key stakeholders and challenges that are specific to these registries. Case Examples 46, 47, and 48 offer some descriptions of rare disease registries. The reader is directed to other chapters regarding relevant good registry practices.

2. Genesis of a Rare Disease Registry

2.1. Rare Disease Registry Objectives and Scope

Rare disease registries are initiated by many organizations, such as patients and their families, patient advocacy groups, clinicians, national health systems, and biopharmaceutical product manufacturers, for many reasons. Often, rare disease patient registries have grown organically. In rare diseases where patients are few, research agendas do not exist, standard case guidelines are absent, and patient communities have not yet formed, patient registries are an intuitive first step for stakeholders trying to understand the number of people affected their geographical distribution, and the basic demographic and clinical characteristics of the disease. The scope of these registries may evolve over time, maturing from an outreach/community-building effort or a means for a basic understanding of patient and disease characteristics, to a supportive mechanism for research funding and attracting health care providers. As with all registries, a single rare disease registry need not fulfill all goals for all potential stakeholders. Ideally, however, a well-designed registry provides an infrastructure that can support different needs in an efficient way and eliminate barriers to scientific progress.

It should be noted that rare disease registries include not only diseases that are inherently rare, but also common diseases that are rare in specific populations, especially those defined by demographics. Thus, plaque psoriasis—common among adults—is rare in children, and breast cancer—common among women—is rare among men. While some of the objectives specific to rare disease registries will apply (e.g., patient identification and recruitment), others may not (e.g., disease classification, measuring disease-specific outcomes).

Registries can be developed to serve multiple purposes. The design of the registry depends upon the maturity of the research plan around the disease, the availability and duration of funding, and to some extent, the number of patients affected. For rare diseases, the perception of relative importance of research often correlates with the number of patients affected or the number of empowered disease advocates.

The specific objectives of rare disease registries typically cluster into the following categories:

  1. To connect affected patients, families, and clinicians. Patients and families of affected individuals are often interested in knowing about others who share their disease. Many rare diseases have a genetic basis. However, even if multiple family members are affected with the condition, the motivation to be connected to others may be quite strong, driven by their personal desire to know more about the condition, its natural history, alternative coping mechanisms and treatment options, and the diversity of clinical courses and outcomes. The need to connect is enhanced if the patient or family has difficulty in finding an expert to provide advice or the doctor or genetic counselor points out how little is known about the rare condition.
    Registry meetings provide an opportunity to talk and to share personal experiences. These meetings may include lectures and discussion among patients and families and with experts in medicine, dentistry, nursing, sociology, and many other fields. The advent of social media has increased patient involvement in these types of activities by encouraging patient-to-patient dialogue and assisting with recruitment for research and support. Patients and families often want to connect to advocate support of patients' services and financial support for patient care and research.
    Similarly, physicians and other clinicians may want to connect with other clinicians to learn more about the disease and possible treatment options. Most clinicians have not seen a wide spectrum of rare diseases, and little information on some diseases may be available in the literature. Registries may offer a connection to essential information and to experts in the disease area to assist health care providers with advising and counseling patients.
  2. To learn the natural history, evolution, risk, and outcomes of specific diseases. Stakeholders often initiate registries to learn the natural history of a rare disease. Typically rare diseases are described in a general way based on their symptoms at the time of diagnosis. With refinement in diagnostic techniques, including genetic, biochemical, and physiological testing, classical disease descriptions are broadened and diseases are better described in terms of the range and likelihood of specific outcomes. Unlike more common diseases, for which criteria for classification will often evolve, such evolution may not be possible for rare diseases, but the acceptance of some general criteria that derive from these studies will inform and help subsequent research. As general and specific therapies emerge, the natural history often changes and the “classical description” may no longer apply. With better therapies for treatment and supportive care, new complications may also be recognized. For treatments that extend life expectancy, what is known about the trajectory of disease can change drastically. A disease registry incorporating patients with rare diseases from many centers allows for gathering stronger and more generalizable safety, diagnostic, and prognostic information.
    For industry, natural history of disease registries are often developed to better understand the burden of disease, elements of disease progression, disease genotypic and phenotypic heterogeneity, and potential endpoints (or surrogate endpoints) that may be used in therapeutic clinical development. Increasingly, these types of disease registries are also used to understand patient and caregiver quality of life and the economic consequences of these diseases, as well as to understand the background risk of specific outcomes (i.e., to provide a reference population) that usually cannot be found or inferred from other sources of data when the disease is rare.
  3. To support research on genetic, molecular, and physiological basis of rare diseases. Research on features of disease, both clinical and basic, is a common objective of a registry. Clinical research depends on having a representative population for determining the timing and frequency of natural events and complications, such as development of autoimmune complications, unusual infections, and related or unrelated malignancies. For this reason, rare disease registries benefit from a comprehensive database that is sufficient to address critical clinical questions, while at the same time not being so all-inclusive that the data cannot be acquired and maintained with reasonable effort on the part of the registry team.
    Patients, researchers, and clinicians share interests in understanding diseases at the genetic, molecular, and cellular level. Such studies usually require a biorepository of materials for research, including tissue (fresh and frozen), DNA, RNA, cellular proteins, and bodily fluids. Creating a meaningful repository for the study of rare diseases requires collection of materials from a sufficient population to permit generalization about the fundamental features and diversity of the disease at the genetic, molecular, and cellular level. A registry is an important complement to any biorepository; similarly, biorepositories are far stronger if they are closely linked to a registry that contains relevant longitudinal clinical or phenotype data. In cases where multiple small or regional registries exist for a specific condition, a centralized biorepository can serve as a common link and research resource. Valid interpretation of biosample research depends on understanding the clinical features of the patients and the heterogeneity of the disease in the study population. In addition, the existence of parallel relevant longitudinal clinical data allows for assessment of genetic and environmental disease modifiers.
  4. To establish a patient base for evaluating drugs, medical devices, and orphan products. Stakeholders are vitally interested in developing drugs, devices and other therapies for rare diseases, and many rare disease registries have been developed to support the drug development process. Patient registries for rare diseases may emerge from suggestion, pressure, or advocacy of affected patients and/or families. Direct influence can be seen when patients and their caregivers decide they want a registry, raise the funds, and push for its creation. Indirect influence can be seen when patients or special interest groups drive government to make research on that disease a priority. Researchers and industry recognize that a population of patients is essential for clinical testing, and industry may provide rare disease groups with support to begin or expand a fledgling registry so that ultimately a potentially useful drug or device can be tested in the disease population.
    Often, developing a treatment for a rare disease will provide information about pathophysiology that informs treatment development of a related disease. If the rare disease is serious with few or no treatment options, regulators may relax some of the requirements for drug registration (as is indicated by the requirements for orphan drug development).

2.2. Rare Disease Registry Stakeholders

Any registry endeavor has a number of stakeholders, often with both convergent and divergent agendas. Stakeholders may include patient advocacy groups (often multiple), regulatory agencies (especially if the registry is being developed to support future drug development and approval or to fulfill postmarketing commitments or requirements), clinicians, scientists, industry, payers, and the individuals and families affected by the disease. Collaboration between stakeholder groups has been critical to the progress made in research and product development, the adoption of important public policy changes in the United States and worldwide, and the promotion of patient access to treatments as they become available.3 Table 20–1 describes potential registry stakeholders and the roles they may play in registries.

Table 20–1. Role of stakeholders in rare disease registries.

Table 20–1

Role of stakeholders in rare disease registries.

The importance of patient registries in rare diseases and the need to support many organizations has also brought umbrella patient organizations (e.g., NORD, the Genetic Alliance, EURORDIS) in as stakeholders, as these groups are charged with advising and supporting the development of registries. As the number of registries increases along with the number of commercial companies to develop and host them, these umbrella organizations are becoming brokers for services and are motivated to identify standards and shared efficiencies to support patient registries for the thousands of rare disorders that need them. In addition, the proliferation of patient registries for rare diseases brings standards development organizations and standards interests into the fold as the need for standards that can facilitate data sharing (i.e., common data elements) between patient registries and other aspects of health care and clinical research has become evident. More broadly, the vision of patient registries that can share data between electronic health records and personal health records, as well as with clinical research or national public health efforts, has engaged a variety of commercial application providers in the field.

Representatives from any of the groups mentioned as stakeholders can function as registry sponsors or developers. A distinction is made between registry sponsors, as the entities who fund plan, and often select data collection content for a registry, and developers, as the technology and computing professionals who build the registry.

Although data from registries are not a substitute for controlled trials, rare disease registry data may be the only source of information (especially about a specific product's use) available to stakeholders. This information may serve to inform industry such that a controlled trial can be determined to be feasible, designed appropriately, and well informed upon inception. Disease registry data complement trials, especially those conducted in rare diseases, for which other sources of data are rare or nonexistent. Industry supports many rare disease patient registries, both disease-based and product-based, as sponsors and developers. This is particularly common in rare disorders for which the clinical development program is often abbreviated and inclusive of only a small, relatively heterogeneous subpopulation of the disease population. These registries are often well received by patient groups who do not have funds to operate a registry independently, but stakeholder objectives are not always aligned. For example, industry-sponsored registries are in some cases treatment- or product-based registries, where patients are included for study based upon treatment exposure. However, some product exposure registries create a fragmented system that does not allow researchers or policymakers to see the entire spectrum of disease.4 These different product registries have different sponsors and collect different data (often at the behest of regulators who seek answers to different questions), rendering them difficult to combine during research. When more than one treatment exists for a given condition, the different postmarketing treatment registries are often not comparable, nor are the full spectrum data (from multiple registries hosted by multiple companies) easily accessible for academic researchers. Additionally, if patients are exposed to multiple treatments, their data might be in multiple registries, but their full experience across treatments is not appreciated.

Disease registries (rather than exposure or treatment registries) create the possibility of assessing the long-term safety and benefit of different treatments, perhaps leading to treatment algorithms that allow more choices for patients and clinicians. Regulators have increasingly recognized the value of disease registries for historical comparator data and long-term evaluation (especially for drug safety) and as a complement to randomized clinical trials to “fill in the blanks” about outcomes that were not addressed in the limited controlled studies. These registries become even more important to regulators (and others involved) when the disease is rare and registries may be the only means by which data can be obtained. The marriage of stakeholder interests may create conflicts of interest for these registries that require careful scrutiny of available resources. If an effective partnership can be established and maintained the creation of clinician and patient/caregiver communities can be a powerful agent in the success of a product in development or evaluation.

Even more effective in rare disease research is a collaborative approach in which multinational and multi-institutional stakeholders combine resources. As resources are combined standardization becomes more important to allow data to be compared across registries. Regulatory organizations such as the U.S. Food and Drug Administration and the European Medicines Agency can guide standardization across multiple postmarket registries within specific disease areas and promote the creation of multisponsor registries where appropriate. Other organizations like PARENT (PAtient REgistries iNiTiative) are facilitating cross-border collaborations to develop comparable and transferrable patient registries. Resources and tools for identifying and sharing patient registry questions, such as the PRISM (Patient Registry Item Specifications and Metadata for Rare Diseases) library of patient registry questions,5 will support these standardization efforts.

Although the creation of a single global registry for each disease (or group of diseases) is theoretically a sound idea, in practice it may not always be feasible or in the best interest of researchers. A viable alternative can be a network of registries and resources, such as TREAT-NMD (Translational Research in Europe—Assessment & Treatment of Neuromuscular Diseases), a network of neuromuscular disease researchers that was launched in early 2007. TREAT-NMD aims to create an infrastructure to promote the development of tools (e.g., core outcome sets) that industry, clinicians, and scientists need to bring novel therapeutic approaches through preclinical development and into the clinic and to establish best-practice care for neuromuscular patients worldwide.6 Similarly, multiple registries could be connected via a centralized biorepository or biobank to provide larger sample sizes to understand disease processes and how they correlate with patient outcomes. As with any collaborative research, the challenges lie in who manages the collaboration, who funds it, and what governance infrastructure is required to bring together researchers who may be reluctant to share their data. The availability of indices of registries [e.g., OrphaNet7 in Europe and the new Registry of Patient Registries (RoPR) in the United States8] is helpful for identification of potential data sources and collaborators.

3. Implementation of a Rare Disease Registry

3.1. Patient Population

Because patient registries can collect clinical information from larger, more heterogeneous populations than those included in a clinical trial, they are becoming increasingly valuable, particularly for diseases affecting very small patient populations, such as lysosomal storage disorders and for specific populations such as children.9 Whereas selection of patients may be highly restrictive in general disease registries, rare disease registries often have more liberal criteria for inclusion. In many cases, a physician diagnosis, rather than the more common strict classification schema, may be sufficient for inclusion in a rare disease registry. Reasons may include: (1) no classification criteria exist; (2) knowledge of the rare disease is so limited that being more inclusive is desirable; and (3) the population is so small that being more inclusive is desirable. With some exceptions, rare disease registries typically do have broad inclusion criteria and attempt to enroll most, if not all, eligible patients within a targeted geographical area.

Although they may not be sufficient for population-based estimates of disease, these data sources can be used to estimate the numbers of affected patients and the number of patients potentially available for research, and can enable the mobilization of disease-specific communities for advocacy. Since a large proportion of recognized rare diseases are genetic in origin, enrolling family members greatly improves understanding of the disease, but may create additional complexities around confidentiality, logistical issues (e.g., different last names and other tracking issues), and considerations for enrollment of minors. The issue of “study fatigue” should also be considered when developing patient enrollment plans. Because of the limited numbers of available patients, some patients may be asked to participate in multiple studies over time. Patients may become overtaxed by frequent participation in studies and reluctant to join new studies.

For registries examining treatment-related outcomes, the challenges in creating an inclusive patient cohort include differences in health care delivery systems, local regulations, and budgetary considerations that create barriers to care and/or specific treatments. For example, if a disease is rare, a drug or device manufacturer may choose not to go through the rigorous process required to have the product approved or priced locally—for example, in a small country—as the number of patients who might ultimately use the product does not support the cost of time and effort. This may create difficulties in enrolling a representative patient cohort from such regions.

3.2. Data Collection

Most registries are tempted to (and often do) include as many data elements as possible in order to glean as much information as possible from their study population. This often leads to increasing respondent and investigator burden, high rates of discontinuation, and substantial challenges in data management. In some registries, these drawbacks may be offset by the ability to continue to recruit additional patients and/or the availability of sufficient numbers of patients already enrolled despite dropout. This is rarely the case, however, with rare disease registries. Thus, balancing the need for a broad dataset with the burden of data collection is highly important for rare disease registries.

In many respects, data collection for rare disease registries is similar to data collection for other types of registries. Like other registries, rare disease registries aim to collect a uniform set of data on each patient. Data elements should be clearly defined to ensure consistency in interpretation across participating sites, and data collection and management procedures should be designed to support the collection of high quality data. Other chapters in this document discuss these concepts in more detail as they apply to registries generally. However, while many of the best practices described elsewhere in this document are applicable to rare disease registries, rare disease registries face unique data collection challenges not addressed by those best practices. In particular, rare disease registries may encounter additional hurdles when attempting to use common data elements, selecting quality of life or patient-reported outcome measures, collecting biomarkers, obtaining long-term followup data, and assuring data quality.

3.3. Creating Efficiencies in Registry Development

A major step in the development of any registry is the selection of the data elements. This task can be time consuming and resource intensive, particularly when multiple stakeholders are involved in defining the data set. As noted in Chapter 4, the primary goals in selecting data elements are to ensure that the necessary data are collected to achieve the objectives of the study and that the data set is not so overly burdensome as to limit participation in the registry. A critical component of developing the data set is defining the data elements and determining how each piece of data will be collected. Many registries develop and define their own data elements. This approach can be costly, and it limits the ability of data from the registry to be linked or compared with data from other registries or data sources. It is more challenging to standardize the data collection for rare diseases, as the understanding of the disease is likely to be limited and, until recently, established standardization efforts were limited.

Common data elements (CDEs) may offer a potential solution to some of these issues. A CDE can be defined as “a data element that can be consistently collected across all clinical studies.”10 CDEs include standard definitions, code lists, and instructions so that the data are collected and stored in the same manner by each participating site, in each study. CDEs may be general, meaning they can be used across disease or therapeutic areas (e.g., demographics, vital signs)11 or disease-specific, meaning they are designed for research in a particular disease area (e.g., congenital muscular dystrophy).12 By using CDEs, registries may be able to reduce the time and effort involved in developing a dataset and to enable the registry data to be linked or compared with data from other studies using the same CDEs.

CDEs are particularly important for rare disease research. CDEs may lower the cost of developing a new registry, making registries more accessible for diseases where funding is limited. CDEs may also enable data from multiple small registry projects to be linked or compared to increase knowledge about the disease. The Institute of Medicine noted the potential importance of CDEs for rare disease research. In the 2010 report, Rare Diseases and Orphan Products: Accelerating Research and Development, the IOM stated “The NIH [National Institutes of Health] should support a collaborative public-private partnership to develop and manage a freely available platform for creating or restructuring patient registries and biorepositories for rare diseases and for sharing de-identified data. The platform should include mechanisms to create standards for data collection, specimen storage, and informed consent by patients or research participants.”1 Recognizing the potential value of CDEs, NIH recently funded the PRISM project. The objective of the PRISM project, which is administered through the National Library of Medicine and supported by the Office of Rare Disease Research (ORDR), is to develop a library of standardized questions that will be relevant to a broad mix of rare diseases and that can be used to develop new registries or to update existing registries. Ultimately, the project aims to develop tools that will support the rapid implementation of new rare disease registries, the revision of existing registries, and interoperability between rare disease registries and other data sources.5, 13

In January 2010, NIH and ORDR hosted a workshop titled “Advancing Rare Disease Research: the Intersection of Patient Registries, Biospecimen Repositories, and Clinical Data,”14, 15 which launched the development of the Global Rare Disease Registry and Data Repository, a Web-based data registry that will link existing registries, future registries, and biorepositories.16 Two significant work results are expected out of this initiative. The first is a 2-year pilot program in collaboration with Patient Crossroads, Children's Hospital of Philadelphia, and WebMD that will develop a Web-based template to allow any patient group to establish its own patient registry. The second work result is a preliminary set of recommended CDEs17 that has been drafted and has undergone revision based on feedback received from public comment. The CDEs are generally applicable to any rare disease registry. This CDE list mixes required and optional elements in the following categories: current contact information; sociodemographic information; diagnosis; family history; birth and reproductive history; anthropometric information; patient-reported outcome; medications, devices, and health services; clinical research participation and biospecimen donation; communication and preferences. ORDR is working closely with the Clinical Data Interchange Standards Consortium (CDISC), which has reviewed the ORDR CDEs18 and is in the process of a similar initiative focused on CDEs for clinical trials. Planned next steps include working with the rare disease community (including clinicians, patients, and advocacy groups) to develop CDEs for specific rare diseases.

While CDEs have significant potential for rare disease registries, they do have some limitations. First, while general CDEs may be relevant for rare disease registries, these CDEs can typically only cover a small portion of a data set necessary for studying a rare disease. The currently available disease-specific CDEs tend to focus on prevalent diseases, such as cancer, cardiovascular disease, and neurological disorders. (Refer to Chapter 4 for a table of currently available CDEs.) Some of these CDEs may be relevant for some rare disease registries, but many may not be useful. Second, CDEs may change over time to reflect changes in practice or new trends in clinical research. Registries with shorter durations (1 to 2 years) may not be affected by changes in CDEs, but rare disease registries are often designed to follow patients for long periods (e.g., several years or until death). To retain the benefits of linkage and comparison, registries that use CDEs would need to update their data collection tools to reflect the changes in CDEs.

In selecting data elements for a rare disease registry, it is useful to consider using CDEs as a first step, before developing new data elements independently. Available CDEs may be relevant for basic information, such as demographics, and for some disease-specific information, and the use of these CDEs is encouraged when possible. When CDEs are not available, a review of the literature and searches of and other similar databases may identify other registries or clinical studies in the disease area. Those studies may be willing to share information on their data sets, so that the new registry can either align with those data elements to support future linkages or comparisons or perhaps learn from issues that have come up in the other studies and apply that knowledge to the development of a new data set. As noted in Chapter 4, other considerations in selecting data elements include feasibility (Are the data elements routinely collected in clinical practice?), burden (What scope of data collection is desirable; what burden on participants is tolerable?), and geographic variations in terminology and practice (Do disease definitions differ? Are data collected the same way in all registry locations? Do terminologies vary by country?).

3.4. Including Quality of Life or Patient-Reported Outcome Measures

Quality of life measures and patient-reported outcome measures (PROs) are increasingly being used in registries to understand patient experiences and preferences. In rare disease research, quality of life data and PROs may be particularly important when well-defined widely accepted clinical outcomes are not available. The progression and mechanisms of rare diseases are often not well understood a situation that inhibits the identification of meaningful clinical outcomes, the development of new therapies, and the assessment of the effectiveness of existing therapies or disease management strategies. Quality of life measures and PROs may provide useful data to show that disease management strategies or treatments are effective at improving patient (and caregiver) outcomes or quality of life.

The selection of quality of life measures or PROs for a rare disease registry can be challenging. Disease-specific measures are often not available, and generic measures that were developed with consideration to more common diseases (e.g., the SF-36) are not detailed enough to capture relevant changes in the patient's (or caregiver's) quality of life. New measures may be difficult and expensive to develop, given the small number of patients, validation requirements, and the need to have measures that can be used in multiple languages. As with the selection of data elements, registries may seek to identify other existing studies in the disease area and use similar measures to allow for future comparisons. When selecting measures, burden on the participant is a major consideration. The inclusion of multiple quality of life measures and PROs can be tempting, but they may deter patient participation if the burden is excessive. Considerations for selecting measures, collecting the data, and analyzing and interpreting the data are further discussed in Chapter 5.

In addition to utilizing a PRO tool, a registry may be used to validate one or more PRO instruments across a large number of centers and in some cases countries. Nonvalidated tools, such as patient diaries and other electronic or paper-based data collection methods (e.g., treatment logs to track compliance, symptom checklists), may also be integrated across the registry or within a subpopulation of interest.

Health economic data may also play an important role in a rare disease registry. While the major goals of the registry may be to improve understanding of the disease or to monitor treatments, an underlying objective may be to build the case for new research in the disease area and the development of new therapies. Health economic data may be useful for more broadly demonstrating the global burden of disease. Because of the rarity of the disease, the burden may not be well understood and global burden of disease data may be used to gain support for funding new research in the disease area. In addition, if therapies are developed for rare diseases that were once only treated with supportive care, some aspects of disease burden may improve, while other considerations, such as long-term disease management, may be introduced.

3.5. Biomarkers

Biomarkers, which may describe risk, exposures, intermediate effects of treatment, and biologic mechanisms, are an important component of rare disease research and may serve as important surrogate endpoints for health outcomes.19 In their report on accelerating rare disease research, the IOM identified biomarkers as an important avenue. When biomarkers have been identified for a rare disease, registries in that disease area should consider collecting biomarker data as part of the registry. Registries in disease areas for which biomarkers have not been identified may also consider collecting biological specimens, physiological tests, or radiographic studies, in the hope of furthering efforts to develop and validate biomarkers.1

When determining whether to collect biomarkers or other biological specimens, registries must consider several factors, addressing the following questions:

  • Does the biosample need to be collected once or on an ongoing basis? If ongoing, how often?
  • Does the biosample need to be examined by a central laboratory? Will multiple laboratories be needed because of geographic constraints (e.g., the fact that samples collected in the European Union cannot be sent to a laboratory in the United States) or time constraints (e.g., that sample processing is required within 24 hours)?
  • What privacy and ethical issues will the collection and storage of biosamples introduce?
  • How will the informed consent document discuss the collection and storage of biosamples? How broad can the language be? Can it address unanticipated use of these samples?
  • How long will the biosample data be stored? For what research purposes may it be used?

As more is learned about a rare disease and its origins, the ability to perform exploratory analyses on existing samples is critical and should be considered when a biorepository is established.

3.6. Collection of Followup Data

Collection of long-term followup data is often an important component of debilitating but not fatal rare disease registries. Many rare diseases are chronic and lifelong, meaning that registries may wish to track patients for several years or even until the patient's death. The collection of long-term followup data for rare diseases raises some unique challenges, including what type of providers should participate (specialist vs. general clinician), how to encourage retention, and minimizing lost-to-followup patients.

Many patients with rare diseases see a specialist in the disease area on a regular but infrequent basis (e.g., annually) and see other clinicians on a more regular basis. The specialist may see several patients with the same disease and may have specialized knowledge of the disease; in that sense, the specialist may be an ideal candidate for registry participation. However, participation by the specialist may result in infrequent data collection on the individual patients or missing data collected by other clinicians. The registry may miss events that occur between specialist visits and may not obtain an accurate picture of the day-to-day impact of the disease. Participation by the clinician (or clinicians) that treats the patient on a regular basis is another option. These clinicians may only see one or two patients with the disease and they may not have specialized knowledge of the condition; however, they may be able to provide more frequent updates on the patient's condition. Both of these approaches have strengths and limitations. The most comprehensive approach is to collect data from both the clinician and the specialist. This allows the registry to gather both the specialist's overall perspective on the patient's condition and the more granular details of the patient's care. However, this approach raises privacy issues, as the registry may need to share the data collected from the specialist with the clinician and vice versa. It may also present recruitment issues, as both providers must participate in order to avoid significant missing data. The registry will also need to plan for both physicians to participate in order to avoid having duplicate patients entered into the registry.

Because the collection of long-term data is often critical to the registry's objectives, the registry must devote sufficient effort to patient and physician retention. Over time, patients and physicians may lose interest in the registry and stop participating. Patients who enrolled in the registry as minors may change physicians and locations on multiple occasions and upon reaching adulthood. Patients may move and begin seeing a new physician, or physicians may retire and stop participating. Direct input and access to registry data by affected individuals is technically possible and would allow for ongoing registry involvement and foster retention of patients. It has been observed that patient/family-entered data is reliable information, but that it may not be as in-depth or conveyed in medical language as is the information provided by a physician. Depending on the objectives of the registry, one approach would be to facilitate patient/family entry of data to the patient registry with better design of data entry forms/screens, appropriate contact and followup with participants, and sharing of study results and summary data from the patient registry with participants.

Chapter 10, Section 3 describes many factors that can encourage retention, as well as some potential pitfalls that may impede it. Rare disease registries with long-term followup components should have plans in place to monitor retention rates and should have consistent procedures for when to consider patients lost to followup. Registries that collect sufficient identifiers may also consider linking to other data sources, such as the National Death Index in the United States, to determine if patients have died. Procedures used to locate missing registry participants should be articulated in policies and procedures documents and communicated to participants. In addition, processes to retain patients as their status changes (e.g., from treating clinician to clinician; from minor to adult) should be clearly stated, and multiple contact points should be available for both the individual and their next of kin/designated secondary contact.

3.7. Data Analysis

Patient registries are critical for accruing a sufficient sample size for epidemiological and/or clinical research for rare diseases. In most cases, the registries are not statistically powered for hypothesis testing, and the analytic goals should focus on the descriptive techniques relevant to observational research. The uptake of common data elements could facilitate the formation of analysis data sets from the combination of multiple data sources in situations in which two or more disease registries exist, thus increasing sample sizes.

Data collected in rare disease registries prior to the introduction of therapies that drastically alter standard of care and/or treatment guidelines can provide useful information regarding the natural history of disease. If these data do not exist, removing the effects of widespread treatment(s) from registry analysis on disease progression, particularly in highly heterogeneous disease, is challenging. An additional challenge in rare disease registries is the fragmentation of the data. Patients may contribute data sporadically, but not be completely lost to followup. If data are combined across registries (or other databases), care should be taken to identify potential duplicate patients prior to analysis, as this is more likely to occur in a limited population. Many of the other considerations for analysis (e.g., controlling for confounding, handling of missing data, loss to followup) are not unique to rare disease registry data and are addressed in other chapters, such as Chapters 2, 3, and 13.

3.8. Data Access and Communication

Because populations with rare diseases are often considered vulnerable and under-resourced and because such populations are smaller, it is important to plan for registry data access and communications. Data ownership, data access, and communication are important issues for all registries, but rare disease registries often must pay special attention to these issues because of the broad range of stakeholders involved and the potential interest to others in the disease. Ownership of the data should be clearly specified during the planning phase of the registry and should be communicated to stakeholders and participants in the registry. In many cases, the data owner is the sponsor of the registry. Some registries, though, may have multiple sponsors, or the sponsor may designate that another group will own the data. In addition to ownership of the actual data, ownership of the intellectual property resulting from the registry (e.g., case report forms, patient-reported outcomes tools, reports, analyses, and associated biosamples) should be clearly specified.

Rare disease registries should also develop and adhere to a data access plan. Many data access scenarios are possible. For example, the registry data may only be accessible to the data owner or the sponsor. Alternately, the registry may develop data sharing policies that allow other researchers to access the data. The registry may limit data sharing to investigators participating in the registry, or may allow outside investigators to access the data. For example, an outside researcher may use data from the registry to assess incidence of a particular complication for the purposes of informing protocol development for a new study. As discussed in Chapter 2, data sharing policies should address who can access the data, for what purposes, and under what circumstances (timeframes, access fees, etc.). For example, will manufacturers be able to access data to inform the design of new clinical trials? Will researchers be able to link the data to other data sources for new studies? These types of questions should be carefully considered and addressed in data sharing policies so that all participants (including patients) are aware of the policies and plans for the registry data. Written registry policies and procedures are encouraged and required by many regulatory entities (e.g., institutional review boards).

Publication rights and plans for disseminating information from the registry should also be considered during the planning phase. This is particularly important for rare disease registries with multiple stakeholders, who may have diverse and conflicting interests. There may also be considerations about academic and other interested parties not included in the registry who may wish to use these data at some later point in time. For example, a registry with strong patient advocacy group support and industry funding may need to balance the desire to publish early (in order to share information with the patient community) with the desire to publish later (in order to protect proprietary information related to treatment development). Clear publication plans that are shared with registry stakeholders can help to avoid disagreements once the registry has begun collecting data, and can promote registry transparency.

Like all registries, transparency is important for rare disease registries, and perhaps especially important.1 Because rare diseases have a limited pool of patients, they need to maintain a highly motivated patient community engaged and actively participating in the registry. Transparency in registry operations, analyses, and publications can help to reassure participants that the registry is fulfilling its objectives and continues to be a worthwhile endeavor. This may take the form of regular updates on registry enrollment and data collection, newsletter updates from principal investigators, and information sharing about abstracts or publications based on registry data. Transparency also requires full disclosure to participants about the use of their data, the registry funding sources, and any underlying goals or motivations for the registry.

3.9. Governance

The governance of a rare disease registry can be extraordinarily simple or, more often, fairly complicated. Complexity stems from the variety of stakeholders involved and their different agendas, as well as the geographical and cultural distances between the interested parties, particularly for international registries. Simplicity depends upon having clear goals and adept leadership. Registry leadership may be in the form of an Advisory Board or other leadership committee. Advisory boards and general governance principles are discussed in Chapter 2, Section 2.6.

Rare disease registries present unique governance challenges because they often represent collaborations with many stakeholders and may be international in scope. Some examples are included below.

  • Funding: If not centrally funded, who takes responsibility for raising money, writing grants, and securing the necessary funds for the operation of the registry? If fully funded, what role in decisionmaking does the financial sponsor(s) have? What are the startup costs versus maintenance costs?
  • Privacy: Patients with rare diseases are more vulnerable than most to being identified by their health information. How does the registry protect the privacy of the individuals and families while at the same time creating a database of information and resources for the benefit of all persons having the rare disease of interest?
  • Outreach: How does the registry identify affected and interested persons for participation in the registry?
  • Information: What database is needed for the registry? What demographic, clinical, and/or longitudinal databases are needed? How will the registry adapt as new data needs are identified?
  • Ownership: Who owns the information collected by the registry? For a tissue repository, who owns the materials in it?
  • Agenda: Who sets priorities and establishes the work plan for the registry? What are the respective roles of the stakeholders in setting the agenda?
  • Collaborations: Does the registry governing body create collaborations or can individual participants make collaborative agreements? What approvals are required? How are conflicts avoided and handled?
  • Publications: Who takes responsibility for determining the publication plan, submitting abstracts, writing journal articles, and otherwise publishing about the activities of the registry? Who does the work? Who gets the credit? Are all of the professional and nonprofessional participants treated equally?

4. The Future of Rare Disease Registries

Existing literature suggests that rare diseases occur infrequently and there is a scarcity of information; however, in reality, difficulty in correct diagnosis and appropriate identification of patients with rare diseases is a global issue that precludes knowledge of these patients. The lack of information reflects the uncertainties in diagnostic criteria and perhaps even inadequacies in data gathering procedures. As the patient community continues to grow throughout the world, fostered by electronic communication and social media, knowledge of the prevalence of rare diseases will increase and access to patients will be more readily available. Improved access to information on rare diseases continues to expand as rare diseases are addressed on a global basis and more people are aware of the informational needs of the rare diseases community.

The increasing interest in rare disease patient registries by a range of stakeholders will likely lead to the development of many more patient registries. In the absence of a central health care system with all demographic and clinical data in one place, individual registries for different diseases are likely, each with a smaller and smaller set of patients. Organizational collaboration and shared resources, plus engagement of the rare disease community, are needed to move research and knowledge forward. These registries may be used to identify new pathways for treatment, develop clinical research tools such as endpoints, scales, or outcome measures, and recruit potential participants for clinical trials. However, the development of each individual registry requires significant effort and resources. For some diseases, well-organized private foundations or manufacturers with an interest in product development or monitoring are capable of developing effective registries. For many other diseases, there are few resources to support an independent registry. Some efforts are underway to develop linked networks of registries for rare diseases. For example, the NIH has put forth the idea of creating a federation of Internet-based registries for rare diseases. The goal of this effort is to reduce the costs of developing and running a registry. The idea was part of the discussion at a January 2010 conference on patient registries and rare diseases sponsored by the NIH's ORDR.20

The proliferation of registries and the need for global multidisciplinary cooperation for rare disease research creates an urgent need for standards and best practices for these types of patient registry projects. The large number of registries and the various purposes and stakeholders for each complicate any attempts to inventory, standardize, or prescribe good design features for patient registries in general. As previously described, ORDR, in collaboration with the rare diseases community, is working to establish the Global Rare Diseases (Patient) Registry and Data Repository to enable analyses of data across many rare diseases. ORDR has developed and posted for public use a set of general CDEs to be used for rare diseases; these have gained support at NIH, CDISC, and in the international community. At a recent meeting of the International Rare Diseases Research Consortium (IRDiRC) in Bethesda, the CDEs were accepted as a starting point for rare diseases. The ORDR also will make available to all patients/patient advocacy groups a Web-based template to establish a patient registry with the ability to link patients' data and medical information to their biospecimens. In addition, ORDR will encourage all individuals and organizations that elect to develop a patient registry to participate in the Registry of Patient Registries to increase public exposure to these vital research tools. The next stage is to develop organ/system–specific and disease-specific CDEs developed as collaborative efforts of patients, research investigators, industry clinicians, and other partners in the rare diseases community. ORDR continues to collaborate with NIH research institutes to identify existing rare disease patient registries and use the common data elements.

Because of the increase in the number of registries, more efficient ways to implement and maintain rare disease registries and maximize utility for all stakeholders will be required. Technological advances, such as means for integrating data sources, should result in processes that are more streamlined for the data provider as well as the analyst. The growth of Web-based patient communities and social media may also be increasingly integrated into registry data collection and conduct, as community building across geographical boundaries continues to become simpler.

Case Examples for Chapter 20

Case Example 46Using registries to understand rare diseases

DescriptionThe International Collaborative Gaucher Group (ICGG) Gaucher Registry aims to enhance the understanding of the variability, progression, and natural history of Gaucher disease, with the ultimate goals of better guiding and assessing therapeutic intervention, and providing recommendations on patient care to the medical community that will improve the outcomes for patients affected by this disease around the world.
SponsorGenzyme, a Sanofi company, Cambridge, MA
Year Started1991
Year EndedOngoing
No. of Sites700+ sites have enrolled patients
No. of PatientsMore than 6,500 with open-ended followup


Rare diseases pose special and unique research challenges. The small number of affected patients often results in limited clinical experience within individual health care centers. Therefore, the clinical description of rare diseases may be incomplete or skewed. The medical literature often consists of individual case reports or small case series, limiting understanding of the natural history of rare diseases. Furthermore, randomized controlled trials with adequate sample size and length of followup to assess treatment outcomes may be extremely difficult or not feasible. The challenge is even greater for rare diseases that are chronic in nature, where long-term followup is especially important. As a result, rare diseases are often incompletely characterized and lack published data on symptomatology, disease manifestations, and long-term treatment outcomes.

Gaucher disease, a rare enzyme deficiency that affects fewer than 10,000 known patients worldwide, illustrates many of the challenges facing researchers involved in rare diseases. Gaucher disease has three clinical presentations: Type 1, non-neuronopathic; Type 2, acute neuronopathic; and Type 3, subacute neuronopathic. Physicians who encounter patients with Gaucher disease typically have just one or two affected patients in their practices; only a few physicians around the world have more than 10 to 20 patients with Gaucher disease in their care. Understanding Gaucher disease is further complicated by the fact that it is a highly heterogeneous and rare disorder with variable progression among patients; a patient cohort from a single center may represent a subset of the entire spectrum of disease phenotypes.

The rarity and chronic nature of Gaucher disease also pose challenges in conducting clinical research. The clinical trial that led to U.S. Food and Drug Administration approval of enzyme replacement therapy (ERT) for Gaucher disease (Ceredase®, alglucerase for injection) in 1991 was a single-arm, open-label study involving only 12 patients followed for from 9 to 12 months. In 1994, a recombinant form of ERT was approved (Cerezyme®, imiglucerase for injection) based on a randomized two-arm clinical trial comparing Ceredase and Cerezyme in 30 patients (15 in each arm) followed for 9 months.

Proposed Solution

Established in 1991, the registry is an ongoing, international, longitudinal disease registry, open to voluntary participation by physicians who care for patients with all subtypes of Gaucher disease, regardless of their treatment status or treatment type. Data on patient demographics; clinical characteristics; treatment regimen; and laboratory, radiologic, and quality-of-life outcome measures are entered and analyzed to address the research challenges of this rare disease. Because of the rarity of Gaucher disease, it is important to create and maintain a reliable, comprehensive registry that serves as an educational resource not only for physicians but also for patients and their families and caregivers. Responsibility for the use, integrity and objectivity of the data and analyses is invested in the ICGG Board of Advisors, which consists of physician-investigators worldwide who are not employees of the sponsor and who advise on the medical and scientific agendas of the registry.


The registry has longitudinal data on more than 6,500 patients from more than 700 health care centers in more than 60 countries. The followup period is open-ended and the registry currently has up to 20 years of followup data from individual patients. The registry has collected more than 50,000 patient-years of followup during the past 21 years. Physician participation and patient enrollment have increased consistently from year to year since 1991.

Analyses of the extensive body of longitudinal data have increased knowledge of the disease in a broad range of topics, including the natural history of Gaucher disease; phenotypic and genotypic variation among patients; diagnosis, treatment, and management of the disease; disease manifestations in children; long-term treatment outcomes for ERT; bone disease and complications associated with the disease; and neuronopathic Gaucher disease. Data generated from the registry have been published in nearly 30 key articles and have provided much needed and important insight into this rare genetic disease.

In 2002, the registry published the clinical outcomes of 1,028 patients treated with ERT with up to 5 years of followup. As more data have been gathered through the registry over the past decade, long-term outcomes in patients with Type 1 Gaucher disease after 10 years of ERT have become available, thus providing new reference benchmarks for assessing clinical responses to ERT for various disease parameters. Other more recent publications based on analyses of data from the registry have focused on important specific aspects of Gaucher disease, such as the effects of early intervention with ERT on the incidence of bone pathology, demographic and clinical characteristics of patients with neuronopathic Gaucher disease, ERT dose-response relationships for disease parameters in patients with Gaucher disease type 1, and phenotypic heterogenicity and genetic variation among patients.

Along with the growth of the registry and the availability of data on Gaucher disease, interest in special patient populations and specific aspects of Gaucher disease continually emerge. As a result, research initiatives into disease subpopulations have been launched recently: the Neurological Outcomes Subregistry, which will begin to evaluate the neurologic manifestations of Gaucher disease and the effects of treatment on these complications; and the Pregnancy Subregistry, which will track the management of Gaucher disease during pregnancy as well as pregnancy outcomes.

The collective clinical experience of the registry led to the development of recommendations for evaluation and monitoring of patients with Gaucher disease. The analysis of registry data on treatment outcomes has facilitated the establishment of therapeutic goals for patients with Type 1 Gaucher disease. Together, these publications have formed the foundation for a consensus- and evidence-based disease management approach, something usually only possible for much more common diseases. In 2008, a benchmark analysis was published that documented the achievement of therapeutic goals after 4 years of ERT among registry patients.

As disease awareness has increased over time, health care providers have sought more direct access to general and patient-specific disease information. Therefore, when the registry changed its technology platform in 2011, it established two key objectives: to simplify data entry to help keep data complete and accurate, and to support the community's increased interest in access to data, aggregate reports, and collaborative expertise. To help meet these goals, the registry ensured that the new platform included functionality that allows physicians direct access to aggregate and patient-specific reporting as well as the ability to download their own data to support their own research. This important application of technology enables the registry to “give back” supportive and research tools to those who contribute to the overall registry data set. This includes the availability of data to address clinical and scientific questions; useful disease management tools, such as interactive patient case reports that a physician can share with other health care providers and with patients themselves; and a larger, better-connected worldwide community of physicians and allied health providers who can share information, identify trends, improve best practices, and build awareness of Gaucher disease that will optimize patient outcomes.

Key Point

For rare or ultra-rare conditions, an international, longitudinal disease registry may be the best or only feasible way to comprehensively increase knowledge about the clinical characteristics and natural history of the disease and assess the long-term outcomes of treatment.

For More Information

Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;113(2):112–9. [PubMed: 12133749].

Vom Dahl S, Weinreb N, Charrow J, et al. Long-term Clinical Outcomes in Type 1 Gaucher Following 10 Years of Treatment with Imiglucerase; Presented at the 2011 Workshop of the European Study Group on Lysosomal Disease (ESGLD); September 3-6, 2011; Langvik, Finland. .

Mistry PK, Deegan P, Vellodi A, et al. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009;147(4):561–70. [PMC free article: PMC2774157] [PubMed: 19732054].

Tylki-Szymanska A, Vellodi A, El-Beshlawy A, et al. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis. 2010;33(4):339–46. [PubMed: 20084461].

Fairley C, Zimran A, Phillips M, et al. Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. J Inherit Metab Dis. 2008;31(6):738–44. [PubMed: 18979180].

Case Example 47Studying rare diseases in an existing registry population

DescriptionThe National Cooperative Growth Study (NCGS) collected data on children with growth disorders who were treated with a specific growth hormone (GH). The purpose of the multicenter, observational, post-marketing surveillance registry was to collect long-term safety and effectiveness information on the GH preparations, with the goals of better understanding the growth response to GH therapy and establishing a safety profile in large populations of different patient diagnostic groups.
SponsorGenentech, Inc.
Year Started1985
Year Ended2010
No. of SitesMore than 550
No. of Patients65,205


The registry was launched following U.S. Food and Drug Administration approval in 1985 of recombinant human growth hormone (rhGH). While the primary purpose of the registry was to monitor the safety and effectiveness of rhGH in all pediatric patients undergoing this treatment, there were insufficient numbers of patients in the clinical trials in each subgroup of patients for whom the drug was indicated to establish a true picture of their medical risks and the interaction or impact of GH on their medical safety. There was particular interest in studying girls with Turner syndrome (TS), a rare chromosomal abnormality known to be commonly associated with multiple medical conditions.

Proposed Solution

Pediatric patients with growth disorders were voluntarily enrolled in the registry when therapy with rhGH was initiated and were followed until discontinuation of therapy. The median length of followup for patients in the registry is 3.3 years, allowing for longitudinal analyses of the natural history of growth disorders and their treatment, and addressing physician queries on the long-term safety and effectiveness of rhGH therapy for their patients. The broad enrollment criteria of the registry enabled capture of a meaningful sample of patients with rare syndromes or diseases. For example, the registry population included over 5,000 patients with TS.


For 25 years, the registry monitored the safety and efficacy of rhGH therapy in 65,205 children with growth disorders treated in more than 550 sites in the United States and Canada, with more than 800 investigators, and accrued over 220,000 patient-years of observation. During this time, analyses resulted in more than 100 publications on safety, dosing, height prediction, outcomes, subgroups of patients, and regulatory safety assessments, with more than 1,200 citations in the research literature. The registry remains the largest North American repository for auxological and clinical outcome data for rhGH-treated children with growth-related disorders.

Analyses were conducted on 5,220 registry patients with TS, resulting in a seminal paper that described the safety profile of GH in this condition and highlighted the natural history of many of the known medical conditions these patients have. The safety profile included assessment of cardiac risks, development of autoimmune disorders, and detected occurrence of a disproportionate number of cases of pancreatitis, compared with the other patient groups in the NCGS. This later finding contributed to a recent label change warning of the risk of pancreatitis for all GH products, including a reference to the published data that suggest higher risk in patients with TS. In addition, a substudy in the registry assessed the degree to which pediatric endocrinologists were following recent guidelines for screening of concurrent medical conditions in TS. This guideline substudy revealed that, in a cohort of 955 girls, screening for cardiac, renal, and hearing abnormalities was not occurring at the expected rate. The clinical implications of these studies were a broader picture of the natural health history of girls with TS as well as specific issues of safety with respect to GH.

The registry closed enrollment in 2010, but the database continues to be a resource for practicing physicians facing patient treatment decisions, averaging 1–2 queries per week from former investigators on the safety and effectiveness of GH treatment. Recent examples of query topics include patients with TS, safety in patients with intractable seizures, medulloblastoma and secondary malignancies associated with GH, primary pulmonary hypertension, and other conditions. One query, on rhGH use in GH-deficient or idiopathic short stature patients treated with stimulants for ADHD, led to a publication that found no significant differences in safety or effectiveness of rhGH treatment for these patients in comparison to non-ADHD treated patients.

Key Point

A large registry can provide a resource of study subjects for focused investigations on specific rare diseases. Even after study closure, registry data can be a useful resource for continued investigations, and for informing treatment in clinical practice.

For More Information

Allen DB, Julius JR, Breen TJ, et al. Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study. J Clin Endocrinol Metab. 1998 Aug;83(8):2824–9. [PubMed: 9709954].

Bell J, Parker KL, Swinford RD, et al. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab. 2010 Jan;95(1):167–77. [PubMed: 19906787]

Bolar K, Hoffman AR, Maneatis T, et al. Long-term safety of recombinant human growth hormone in Turner syndrome. J Clin Endocrinol Metab. 2008;93(2):344–51. [PubMed: 18000090].

Frindik JP, Morales A, Fowlkes J, et al. Stimulant medication use and response to growth hormone therapy: An NCGS database analysis. Horm Res. 2009;72:160–6. [PubMed: 19729947].

Parker KL, Wyatt DT, Blethen SL, et al. Screening girls with Turner syndrome: the National Cooperative Growth Study experience. J Pediatr. 2003 Jul;143(1):133–5. [PubMed: 12915841].

Romano AA, Dana K, Bakker B, et al. Growth response, near-adult height, and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone. J Clin Endocrinol Metab. 2009 Jul;94(7):2338–44. [PubMed: 19401366].

Case Example 48Site motivation and retention in rare disease registries

DescriptionThe Digital Ulcers Outcome (DUO) Registry collects data on patients with systemic sclerosis in an effort to describe digital ulcers disease history, clinical and patient-reported functional assessment status and treatment pattern at the time of enrollment, disease course, and patient management during followup. For patients treated with bosentan, data are collected on physician adherence to labeling guidelines and safety events.
SponsorActelion Pharmaceuticals
Year Started2008
Year EndedOngoing
No. of SitesMore than 350
No. of Patients3,609


Systemic sclerosis (scleroderma) is a rare disease affecting less than 2 in 10,000 persons worldwide. Digital ulcers affect nearly 30 percent of patients with this disease, resulting in substantial morbidity such as gangrene and amputation. Despite the severity of digital ulcers, very little is known about this complication, due to the rarity of the underlying condition. To improve understanding of this condition, data are needed from specialized participating scleroderma centers (sites).

The DUO Registry was mandated by the European Medicines Agency (EMA) as a post-approval licensing requirement for the expanded indication of bosentan to treat digital ulcers. The registry, which operates in 18 European countries, is observational and voluntary in nature, and participating sites are reimbursed solely for data entry time. After 4 years of operation, motivation of the participating physicians started to stagnate, and the sponsor observed a decrease in followup data entry. Because the registry was mandated by the EMA and because of the paucity of outcomes data available about digital ulcers, the sponsor sought to increase participation and in particular, increase the collection of followup data.

Proposed Solution

The sponsor identified academic and professional interest in the registry's findings around digital ulcer management as one of the primary motivators for investigators to participate in the study. To respond to this interest, the sponsor implemented new efforts to engage investigators and regularly inform them of the study's progress. Efforts included the use of newsletters to provide enrollment updates and tips on using the electronic data capture system, presentation of abstracts in scientific congresses, and distribution of letters from the registry steering committee to the investigators encouraging them to enter followup data. An in-person investigator meeting was held where the registry's scientific committee discussed registry findings with the investigators. The sponsor also established a process for investigators to suggest publication ideas and determined that all publications of registry data would include the phrase “and DUO Registry investigators” in the author byline.


From 2011 to 2012, the proportion of patients having at least one followup visit increased from 63 percent to 73 percent, and the mean number of visits per patient increased from 1.7 to 2.6. The registry has now enrolled more than 3,600 patients.

The steering committee and registry investigators published the first original article on registry data in January 2012, reporting on data from 2,439 patients and confirming the disease burden of digital ulcers in systemic sclerosis patients. The sponsor had received feedback that the shared authorship is valuable to some investigators and a major motivating factor for their participation in the registry.

A poster highlighting the current variation in treatment of digital ulcers across Europe and stressing the need for a concentrated approach to establish disease management practices was presented at the European League Against Rheumatism 2012 Annual Congress.

Key Point

Site engagement is particularly important in rare disease registries, because of the limited number of patients. Consistent communication highlighting study objectives and achievements, visibility at scientific meetings, and sharing authorship or acknowledgement on publications can bolster investigators' motivation.

For More Information

Denton CP, Krieg T, Guillevain L, et al. Demographic, clinical and antibody characteristics of patients with digital ulcers in systemlic sclerosis: data from the DUO registry. 2012 Ann Rheum Dis;71:718–21 [PMC free article: PMC3329234] [PubMed: 22247218].

Matucci-Cerinic M, Guillevin L, Denton CP, et al. Management of digital ulcer disease varies across Europe: findings from the DUO registry; Poster presented at The European League Against Rheumatism 2012 Annual Congress; Berlin, Germany. 6-9 June 2012; [August 8, 2012].

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