Chapter 2: Planning a Registry

1. Introduction

There is tremendous variability in size, scope, and resource requirements for registries. Registries may be large or small in terms of numbers of patients or participating sites. They may target rare or common conditions and exposures. They may require the collection of limited or extensive amounts of data, operate for short or long periods of time, and be funded generously or operate with limited financial support. In addition, the scope and focus of a registry may be adapted over time to reach broader or different populations, assimilate additional data, focus on or expand to different geographical regions, or address new research questions. While this degree of flexibility confers enormous potential, registries require good planning to be successful.

When planning a registry, it is desirable to follow these initial steps: (1) articulate the purpose of the registry; (2) determine if a registry is an appropriate means to achieve the purpose; (3) identify key stakeholders; and (4) assess the feasibility and sustainability of a registry.

Once a decision is made to proceed, the next considerations in planning are to (5) build a registry team; (6) establish a governance and oversight plan; (7) define the scope and rigor needed; (8) define the dataset, patient outcomes, and target population; (9) develop a study plan or protocol; and (10) develop a project plan. Of course, the planning for a registry is often not a linear process. Many of the steps described in this chapter occur in parallel.

Registry planners should also recognize the importance of periodic critical evaluations of the registry by key stakeholders to ensure that the objectives are being met. This is particularly important for patient registries that collect data over many years. When registry objectives are no longer being met or when clinical or other changes affect the registry (e.g., changes in treatment practices, the introduction of a new therapy), the registry may need to be adapted, or the registry may stop collecting new data.

Useful resources for registry planners include the Guidelines for Good Pharmacoepidemiology Practice from the International Society of Pharmacoepidemiology;¹ the Updated Guidelines for Evaluating Public Health Surveillance Systems (especially the appendixes, which provide various checklists);² A Guide to the Project Management Body of Knowledge (PMBOK Guide);®³ the Patient-Centered Outcomes Research Institute (PCORI) Methodology Standards for patient-centered outcomes research;⁴ and the Good ReseArch for Comparative Effectiveness (GRACE) principles for comparative effectiveness research.⁵

2. Steps in Planning a Registry

Articulate the Registry's Purpose

One of the first steps in planning a registry is articulating its purpose. Having a clearly defined goal and/or purpose and supporting rationale makes it easier to evaluate whether a registry is the right approach for capturing the information of interest.⁶'⁷ In addition, a clearly defined purpose helps clarify the need for certain data. Conversely, having a clear sense of how the data may be used will help refine the stated purpose.

A registry may have a singular purpose or several purposes.⁸ In either case, the overall purpose should be translated into specific objectives or questions to be addressed through the registry. Note, even if a registry is primarily derived from electronic health record (EHR) data, the purpose(s) of the registry will drive many of the decisions made in data acquisition, normalization, cohort identification and so forth. This process needs to consider the interests of those collaborating in the registry and the key audiences to be reached.⁹ Clear objectives are essential to define the structure and process of data collection and to ensure that the registry effectively addresses the important questions through the appropriate outcomes analyses. Specific objectives also help the registry to avoid collecting large amounts of data of limited value. The time and resources needed to collect and process data from a registry can be substantial.¹⁰ Attempts to be all inclusive may add cost but not value, resulting in overly burdensome data collection that can reduce quality and erode compliance. Thus, the identification of a core dataset is essential. The benefits of any data element included in the registry must outweigh the costs of including it.

Registry planners should establish specific objectives by considering what key questions the registry needs to answer. These questions will determine the type of registry (e.g., whether single focus or comparative), the data elements to be captured, and the types of analysis to be undertaken. Examples of key or driving questions are listed below:

What is the natural course of a disease, and how does geographic location affect the course? Does a treatment lead to long-term benefits or harm, including delayed complications? How is disease progression affected by available therapies? What are significant predictors of poor outcomes? What is the safety profile of a specific therapy? Is a specific product or therapy teratogenic? How do clinical practices vary, and what are the best predictors of treatment practices? Are there disparities in the delivery and/or outcomes of care? What characteristics or practices enhance adherence? How do quality improvement programs affect patient outcomes? What process and outcomes metrics should be incorporated to track quality of patient care? Should a procedure or product be a covered benefit in a particular population? Was an intervention program or risk-management activity successful? What are the resources used/economic parameters of actual use in typical patients?

Determine if a Registry Is an Appropriate Means To Achieve the Purpose

Two key questions to consider are whether a registry (or other study) is needed to address the purpose and, if the answer is yes, whether prospective data collection through a registry is an appropriate means of accomplishing the scientific objectives. Every registry developer should consider the following questions early in the planning process:

Do these data already exist? If so, are they of sufficient quality to answer the research question? Are they accessible, or does an entirely new data collection effort need to be initiated?

For example, could the necessary data be extracted from EHRs or administrative health insurance claims data? In such cases, registries might avoid re-collecting data that have already been collected elsewhere and are accessible. Thought should be given to adapting an existing registry and/or linking to other relevant data sources (including "piggybacking" onto other registries). Literature searches and searches of research databases, such as ClinicalTrials.gov, are helpful for identifying existing studies that may be useful sources of data. When the required data have not been sufficiently collected or are not accessible for the desired purpose, it is appropriate to consider creating a new registry.

The next step is to consider whether the purpose would be well served by a registry. When making this decision, it is important to fully define the specific research question(s) of interest and to consider the state of current knowledge and gaps in evidence. Other factors that may influence this decision include the breadth of the target population of interest, the length of an observational period needed to achieve the objective, the variety and complexity of treatments used, the approximate amount of funding available to address these objectives, and the urgency of decisions that will be made based on the resulting evidence. Registries may be the most appropriate choice for some research questions. For example, registries are particularly useful in situations where a comprehensive, flexible research design is needed,¹¹'¹² or when the purpose is to discover how a product works in a wide variety of subgroups. (See Chapter 3 for a discussion of research questions appropriate for registries.) In some cases, a hybrid approach, such as a registry that incorporates data collected retrospectively as well as prospectively, will be required.

A research strategy, as opposed to a single study, may be necessary to address some research questions. For example, some research questions may require an interventional approach to address concerns about efficacy combined with an observational approach to examine long-term outcomes and quality of life in a broad patient population. When making a decision about study design, it is important to select the approach or combination of approaches best able to answer the specific research questions, from both scientific and practical standpoints. A careful evaluation of the possibilities for data collection and registry design, the degree of certainty required, and the timeframe in which this certainty is expected can help in selecting an appropriate study design.

Historically, there has been a lack of consensus standards for conducting and reporting methods and results for registries. Therefore, registries have been more variable in implementation and more difficult to assess for quality than randomized controlled trials. In recent years, advances in epidemiological and biostatistical methods have broadened the scope of questions that can be addressed through observational studies such as registries. Stratification, propensity score matching, and risk adjustment are increasingly useful approaches for addressing confounding issues and for creating comparably homogeneous subgroups for analysis within registry datasets, and advances in bias analysis are being used to help interpret results from observational studies such as registries.¹³⁻¹⁵ (See Chapters 3 and 13.) These techniques may allow registries to be used to support investigations of comparative safety and effectiveness. Following good registry practices, as described in this User's Guide, can strengthen scientific rigor (Chapter 14).

Identify Key Stakeholders

As a means of identifying potential stakeholders, it is important to consider to whom the research questions matter. It is useful to identify these stakeholders at an early stage of the registry planning process, as they may have important input into the type and scope of data to be collected, they may ultimately be users of the data, and/or they may have a key role in disseminating the results of the registry.

One or more parties could be considered stakeholders of the registry. These parties could be as specific as a regulatory agency that may be assessing its potential use in collecting relevant premarket data for regulatory submissions or in monitoring postmarketing studies or as broad as the general population, or simply those patients with the conditions of interest. Often, a stakeholder's input directly influences whether development of a registry can proceed, and it can have a strong influence on how a registry is conducted. A regulatory agency looking for management of a therapeutic product with a known toxicity profile may require a different registry design than a manufacturer with general questions about how a product is being used.

Typically, there are primary and secondary stakeholders for any registry. A primary stakeholder is usually responsible for creating and funding the registry. The party that requires the data, such as a regulatory authority, may also be considered a primary stakeholder. A secondary stakeholder is a party that would benefit from knowledge of the data or that would be impacted by the results but is not critical to establishing the registry. Treating clinicians and their patients could be considered secondary stakeholders. A partial list of possible stakeholders, both primary and secondary, follows:

Public health or regulatory authorities Product manufacturers Healthcare service providers Payer or commissioning authorities Patients/caregivers Patient advocacy groups Treating clinician groups Academic institutions or consortia Professional societies Funding agencies

Although interactions with potential stakeholders will vary, the registry will be best supported by defined interactions and communications with these parties. Defining these interactions during the planning stage will ensure that adequate dialog occurs and appropriate input is received to support the overall value of the registry. Interactions throughout the entire duration of the registry can also assure stakeholders that the registry is aligned with the purposes and goals that were set out during the planning stages and that the registry complies with all required guidance documents, rules, and/or regulations.

Engagement with patient stakeholders is an increasing area of interest for some registries. The concept of patient-centered research has gained attention in recent years, most notably with the establishment of the Patient-Centered Outcomes Research Institute (PCORI) in 2010. PCORI is an independent, nonprofit organization that funds patient-centered comparative effectiveness research. As a condition of funding, all PCORI awardees must actively engage patients and other stakeholders in all phases of a research project. In addition to the work of PCORI, many other efforts are encouraging the active participation of patients, their caregivers, and patient advocates in clinical research and regulatory decision making. For instance, there has been considerable interest on the part of some regulatory agencies in adopting "adaptive approaches" for drug approval and reimbursement decisions and in factoring patient preferences in weighing benefits and risks of medical devices. These approaches hinge on the early and continuous engagement of patients and other key stakeholders throughout the life-span of drug development.¹⁶'¹⁷ The U.S. Food and Drug Administration (FDA) has taken several steps to formalize the integration of patient perspectives into the regulatory process, including establishing a Patient Engagement Collaborative.¹⁸ At the same time, an increasing number of well-organized, vocal patient advocacy groups are actively contributing to the research landscape by funding grants and facilitating collaborations across academic sites; serving as clinical trial recruitment partners, particularly for rare conditions; and enhancing capacity to develop biomarkers or other clinical screening and monitoring tests for therapeutic products.¹⁹

As a result of these initiatives and other efforts, investigators are increasingly integrating a patient-centered approach into their clinical research and seeking patient perspectives on how a registry can meet patients' needs and expectations, how investigators can best engage with patients, how to best collect the required data, and how the registry could provide additional value to patients beyond data collection. More information on engaging patient partners in the design and conduct of patient registries can be found in 21st Century Registries, an eBook addendum to the User's Guide.²⁰

Assess Feasibility

A key element in determining the feasibility of developing a new registry relates to funding. Registries that meet the attributes described in this User's Guide will most likely require significant funding. The degree of expense incurred will be determined by the scope of the registry, the rigor of data collection, and any audits that may be required. Traditionally, the cost of the registry was driven largely by the number of sites, the number of patients, and the scope of data collected. When using data from secondary sources, the primary cost drivers are the number of health IT systems to be integrated; the amount of effort needed to clean, standardize, and normalize the data; the need to extract data from unstructured fields; and the need to include specialized data such as images. Funding will be affected by whether the registry adapts to new issues over time and whether multiple funding sources participate. Funding needs should also be examined in terms of the projected life of the registry and/or its long-term sustainability.

There are many potential funding sources for registries. Funding sources are likely to want to share in planning and to provide input for the many choices that need to be made in the implementation plans. Funding sources may negotiate to receive access to deidentified data as a condition for their participation. Funding models for registries may vary significantly, and there is no preferred approach. Rather, the funding model for a registry should be dictated by the needs of the registry. Potential sources of funding include:

Foundations: Nonprofit disease foundations may be interested in a registry to track the natural history of the disease of interest as well as the impact of therapeutic interventions. Registries may be used to track practice patterns and outcomes for quality improvement initiatives. Ongoing registries can sometimes serve the additional purpose of assisting in recruitment for clinical trials.²¹

Government: Federal agencies, such as the National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), Centers for Medicare & Medicaid Services (CMS), Agency for Healthcare Research and Quality (AHRQ), FDA, and State agencies, may be interested in a registry to provide seed funding for early development or to determine long-term outcomes of agents, devices, groups of drugs, or procedures. While the pharmaceutical industry or device manufacturers collect most long-term data on drug and device safety, many research questions arise that could potentially be suitable for government funding, ranging from clinical or comparative effectiveness to natural history of disease to the performance of healthcare providers based on accepted measures of quality of care. To determine if an agency might be interested in funding a registry, look for Requests for Proposals (RFPs) on its website. An RFP posting or direct communication with the appropriate agency staff may provide a great deal of specific information as to how a submission will be judged and what criteria would be needed in order for a proposal to be favorably ranked. Even if an RFP is not posted, contacting the appropriate agency staff may uncover potential interest in a registry to fill an unmet need.

Health plan providers: Under certain circumstances, health plan providers may be interested in funding a registry, since practical clinical research is increasingly viewed as a useful tool for providing evidence for health coverage and healthcare decisions.²²

Patient groups: Patients may be able to contribute funding to focus on rare diseases or patient subgroups of interest for more common conditions. They may also contribute value in-kind.

Private funding: Private philanthropic individuals or charitable foundations and trusts may have an interest in furthering research to better understand the effects of a particular intervention or sets of interventions on a disease process.

Product manufacturers: Product manufacturers may be interested in studying the natural history of the disease for which they have (or are developing) a product; demonstrating the effectiveness and/or safety of existing products in real-world use through Risk Evaluation and Mitigation Strategy (REMS) programs as part of postmarketing commitments or requirements or through studies; evaluating the effectiveness of REMS programs or risk minimization strategies; or assisting providers in evaluating or improving quality of care.

Professional societies: Healthcare professional associations are increasingly participating in developing or partnering with registries for scientific and quality measurement or improvement purposes.

Professional society/pharmaceutical industry "hybrids": Situations may exist in which a product manufacturer funds a registry designed and implemented by a professional society to gain insight into a set of research questions.

Multiple sponsors: Registries may meet the goals of multiple stakeholders, and such stakeholders may have an interest in sharing the funding. Registries for isotretinoin and antiretrovirals in pregnancy are examples, as is INTERMACS™, a registry for patients who are receiving mechanical circulatory support device therapy to treat advanced heart failure.²³ While multiple sponsorship can decrease the costs for each funding source, their varied interests and needs almost always increase the complexity and overall cost of the registry.

A public-private partnership is a venture that is funded and operated through a collaboration between a public agency and a private-sector organization. While some public-private partnerships for registries currently exist (e.g., State-level immunization registries, bioterrorism surveillance efforts), there is great potential for growth in this approach. Both government and private sources have shown increasing interest in registries for improved safety monitoring, for comparative effectiveness goals, and for streamlining the costs of the drug development process.²⁴⁻²⁹ Several legislative actions have stated or suggested the role of public-private partnerships for activities such as registry development.³⁰ There are many good reasons for multiple stakeholders, including government agencies, providers, and industry, to work together for certain purposes. Thus, it is anticipated that shared funding mechanisms are likely to become more common. Chapter 9 provides more detail on the use of public-private partnerships to support registries.

Build a Registry Team

Several different kinds of knowledge, expertise, and skills are needed to plan and implement a registry. In a small registry run by a single individual, consultants may be able to provide the critical levels of expertise needed to plan all components of the registry. In a large registry, a variety of individuals may work together as a team to contribute the necessary expertise. Depending on the size, scope, and purpose of the registry, few, some, or all of the individuals representing the components of expertise described below may be included at the time of the planning process. Whatever number of individuals is eventually assembled, it is important to build a group that can work together as a collegial team to accomplish the goals of the registry. Additionally, the team participants must understand the data sources. By understanding the goals and data sources, the registry team will enable the data to be used in the most appropriate context for the most appropriate interpretation. The different kinds of expertise and experience that are useful include the following:

Project management: Project management will be needed to coordinate the components of the registry; to manage timelines, milestones, deliverables, and budgets; and to ensure communication with sites, stakeholders, oversight committees, and funding sources. Ongoing oversight of the entire process will require a team approach.

Subject matter: A registry must be designed so that it contains the appropriate data to meet its goals as well as the needs of its stakeholders. For example, experts in the diagnosis and treatment of the clinical disease to be studied who are also familiar with the potential toxicities of the treatment(s) to be studied are critical to the success of any registry collecting that data. The population under study must be clearly defined and ascertained before subjects are included in the registry for the data to have external validity. Clinical experts must be able to apply all of the latest published clinical, toxicity, and outcome data to components of the registry and determine which elements are necessary, desirable, or superfluous. Additionally, depending on the outcomes and registry purpose, it is often useful to have patient representatives or advocates.

Registry science: Epidemiology and biostatistics expertise specific to the subtleties of patient registries and observational research is very important in the design, implementation, and analysis of registry data. Epidemiologists can provide the study design and can work in collaboration with biostatisticians to develop a mutual understanding of the research objectives and data needed. Health outcomes researchers and economics researchers can also lend valuable expertise to the registry team. These scientists should work with the subject matter experts to ensure that appropriate analytic methods are being used to address the clinical issues relevant to achieving the goals of the registry.

Data collection and database management: The decision to include various data elements can be made in consultation with experts in this field to place "critical fields" in a prominent and logical position on the data form for both paper-based and electronic data collection tools and to determine the most appropriate source of data that will be extracted from other sources. (A final determination of what is usable and workable for data collection should be approved by all members of the team.) These experts may also need to write specific programs so that the data received from the registry are identified, grouped, and stored appropriately. They may generate reports for individuals who track registry participation, and they may provide data downloads periodically to registry analysts. This team will also be responsible for implementing and maintaining firewalls to protect the data according to accepted levels of security for similar collections of sensitive data. Registries that incorporate secondary data sources may also require support from clinical informaticists to clean and standardize these data.

Legal issues/patient privacy: It is critical that either information that identifies individual patients be excluded or applicable legal requirements for the inclusion of patient identifiable information be met (e.g., obtaining informed consent or Health Insurance Portability and Accountability Act [HIPAA] authorization, where required). The complexities of this topic are dealt with in detail in Chapters 7 and 8. Legal and privacy expertise is needed to protect the patients and the owners of the database by ensuring that the registry complies with all Federal and State laws applicable to patient information.

Quality assurance: As discussed in Chapter 11, quality assurance of procedures and data is another important component of registry success. Expertise in quality assurance will help in planning a good registry. The goals for quality assurance should be established for each registry, and the efforts made and the results achieved should be described.

Establish a Governance and Oversight Plan

Governance refers to guidance and high-level decision making, including purpose, funding, execution, and dissemination of information. A goal of proper governance and oversight should be transparency to stakeholders in operations, decision making, and reporting of results. Registries fulfill governance roles in a variety of ways depending on the purpose and size of the registry. Chapter 9 provides more information on registry governance.

Consider the Scope and Rigor Needed

Scope of Data

The scope of a registry may be viewed in terms of size, setting, duration, geography, and financing. The purpose and objectives of the registry should frame the scope, but other factors (aside from feasibility) may ultimately shape it. For example, the scope may be affected by:

Regulatory requirements, such as those imposed by the FDA as a condition of product marketing. Reimbursement decisions, such as national coverage decisions by CMS or "Prior Authorization" requirements used by health insurers in some situations. National research interests, such as those driven by NIH. Public health policy, such policies issued by the CDC.

The scope is also affected by the degree of uncertainty that is acceptable to the primary stakeholders, with that uncertainty being principally driven by the quantity, quality, and detail of the data collection balanced against its considered value and funding. Therefore, it is critical to understand the potential questions that may or may not be answerable because of the quantity and quality of the data. It should also be noted that the broader the audience of stakeholders, the broader the list of questions that may need to be included. This increased breadth can result in an increase in the number of patients who need to be enrolled and/or data points that need to be collected in order to meet the objective of the registry with an acceptable level of precision.

Some of the specific variables that can characterize the scope of a registry include:

Size: This refers to the number and complexity of data points, the frequency of data collection, and the enrollment of investigators and patients. A registry with a large number of complex data points may allow for detailed and thoughtful analyses but may be so burdensome as to discourage investigator and patient enrollments. In turn, a small registry with few patients and data points may be easier to execute, but the data could lack depth and be less meaningful.³¹ Size also determines the precision with which measures of risk or risk difference can be calculated.

Duration: The planning of a registry must reflect both the length of time that the registry is expected to collect the data in order to achieve its purpose and the time needed to perform analyses of the data collected. Some registries may be time-limited by commercial interests, such as when the product under study is approaching the end of its patent life.

Setting: This refers to the specific setting through which the registry will recruit investigators and patients as well as collect data (e.g., hospital, doctor's office, pharmacy, home). Some registries operate within a single setting (e.g., doctor's offices), while others operate in multiple settings (e.g., enroll patients in a doctor's office and follow them through direct-to-patient outreach or collection from or linkage to data from other organizational settings).

Geography: A registry that collects data in one country is very different in scope from a registry that collects data from multiple countries, in terms of setup, management, and analysis. A multinational registry poses challenges (e.g., language, cultural, time zone, regulatory) that must be taken into consideration in the planning process.³²

Cost: The scope of a registry will determine the cost of creating and managing the registry and analyzing the data. Budgetary constraints must be carefully considered before moving from conception to reality. Additionally, the value of the information is a major factor in the financial decision making. Certain choices in planning, such as building on existing infrastructure and/or linking to data sources relevant to the purposes of the registry, may increase the net return.

Richness of clinical data needed: In some situations, the outcome may be relatively simple to characterize (e.g., death). In other cases, the focus of interest may be a complex set of symptoms and measurements (e.g., for Churg-Strauss Syndrome) or may require specialized diagnostic testing or tissue sampling (e.g., sentinel node in melanoma). Some outcomes may require assessment by an independent third party. Depending on the objectives of the registry, collection and storage of biological samples may be considered. (See 'Scientific Rigor' below.) The collection of biosamples and the resulting genomic data is a rapidly evolving field, and registry developers should consult both technical and legal experts regarding how to include biosamples and genomic data in a registry.

When Data Need To Be Available for Analysis

Meaningful data on disease progression or other long-term patient outcomes may not be available through a registry for many years, whereas safety data could be examined periodically over time. Therefore, the type of data on patient outcomes and when they will be available for analysis should be addressed from the perspective of the intended uses of the data in both the short term and long term. For industry-sponsored registries, if planning begins at an early stage, it may be possible to consider whether to align registry questions with those from the clinical trial setting (where appropriate) so that some data can carry over for more comprehensive longitudinal analyses.

Scientific Rigor

The content of the data to be collected should be driven by the scientific analyses that are planned for the registry, which, in turn, are determined by the specific objectives of the registry. A registry designed primarily for monitoring safety will contain different data elements from one designed primarily for monitoring effectiveness. Similarly, the extent to which data need to be validated will depend on the purpose of the registry and the complexity of the clinical information being sought. For some outcomes, clinical diagnosis may be sufficient; for others, supporting documents from hospitalizations, imaging studies, referrals, or biopsies may be needed; and for others, formal adjudication by a committee may be required. Generally, registries that are undertaken for regulatory decision making will require increased attention toward diagnostic confirmation (i.e., enhanced scientific rigor).

Define the Core Dataset, Patient Outcomes, and Target Population

Core Dataset

Elements of data to be included must have potential value in the context of the current scientific and clinical climate and must be chosen by a team of experts, preferably with input from experts in biostatistics, epidemiology, and the clinical area of interest. Each data element should relate to the purpose and specific objectives of the registry. Ideally, each data element should address the central questions for which the registry was designed. It is useful to consider the generalizability of the information collected, as appropriate. For example, when seeking information on cost-effectiveness, it may be preferable to collect data on resource utilization rather than actual costs of this utilization, since the broader descriptor can be more easily generalized to other settings and cost structures. While a certain number of "speculative" fields may be desired to generate and explore hypotheses, these must be balanced against the burden of capturing superfluous data. A plan for quality assurance should be considered in tandem with developing the core dataset.

The core dataset variables ("need to know") define the information set needed to address the critical questions for which the registry was created. Determination of the core dataset variables should be guided by a clear statement of the primary research questions being posed and the analytic plans for addressing those questions. At a minimum, registry planners must account for these fields when calculating the resource needs and overall design of the registry. If additional noncore ("nice to know") variables, such as more descriptive or exploratory variables, are included, it is important that such data elements align with the goals of the registry and take into account the burden of data collection and entry at the site level or, in the case of secondary data sources, the resources required to obtain and process these data. A parsimonious use of "nice to know" variables is important for several reasons.

First, when data elements change, there is a cascade effect on all dependent components of the registry process and outputs. For example, the addition of new data elements may require changes to the data collection system, retraining of site personnel on data definitions and collection practices, adjustments to the registry protocol, and amendment submissions to institutional review boards. Such changes often require additional financial resources. Ideally, the registry would both limit the total number of data elements and include, at the outset, data elements that might change from "nice to know" to "need to know" during the course of the registry. In practice, this is a difficult balance to achieve, so most registries should plan adequate resources to be used for change management.

Second, a registry should avoid attempting to accomplish too many goals, or its burden will outweigh its usefulness to the clinical sites and researchers. Examples exist, however, of registries that serve multiple purposes successfully without overburdening clinicians. (See Case Example 1.)

Third, even "need-to-know" variables can sometimes be difficult to collect reliably (e.g., use of illegal substances) or without substantial burden (e.g., unusual laboratory tests). Even with a limited core dataset, feasibility must still be considered. (See Chapter 5.)

Fourth, it is useful to consider what data are already available and/or collected and what additional data need to be collected. When determining additional data elements, it is imperative to consider whether the information desired is consistent with general practice or whether it might be more intensive or exceeding usual practice. For some purposes, collecting specific laboratory results or additional visits may be necessary, but could change how the registry is perceived by institutional review boards or ethics committees. The distinction between "interventional" and "observational" is straightforward in terms of random assignment to treatment, but some registries with requirements that exceed a threshold of usual practice may be subject to additional requirements more typical of "interventional" research. The determination that a registry should be considered "interventional" from a regulatory perspective can add significant burden and cost to the registry program, and, therefore, the tradeoffs must be carefully considered in planning schedules for registry visits and the collection of data and/or specimens. Registries should carefully consider the potential for different interpretations of "interventional" and "observational."

Finally, it is important to consider patient privacy, national and international regulatory requirements, and ethical considerations to ensure that the registry data requirements do not jeopardize patient privacy or put institutional/ethics reviews and approvals at risk.

Patient Outcomes

The outcomes of greatest importance should be identified early in the concept phase of the registry. Delineating these outcomes (e.g., primary or secondary endpoints) will force registry designers to establish priorities. Prioritization of interests in the planning phase will help focus the work of the registry and will guide study size requirements. (See Chapter 3.) Identifying the patient outcomes of the greatest importance will also help to guide the selection of the dataset. Avoiding the temptation to collect "nice to know" data that are likely of marginal value is of paramount importance, yet some registries do, in fact, need to collect large amounts of data to accomplish their purposes. Possessing adequate data in order to properly address potential confounders during analysis is one reason that extensive data collection is sometimes required.³³

Methods to ascertain the principal outcomes should be clearly established. The diagnostic requirements, level of data detail, and level of data validation and/or adjudication should also be addressed. The issues of ascertainment noted here are important to consider because they will have a bearing on some attributes by which registries may be evaluated. These attributes include sensitivity (the extent to which the methods identify all outcomes of interest) and external validity (generalizability to similar populations), among others.

As discussed in Chapter 4, relying on established guidelines and standards to aid in defining outcomes of interest has many benefits and should be considered.

The Role of Patient-Reported Outcomes in Registriesⁱ

A patient outcome, as discussed above, refers to any outcome related to the patient, whether reported by the patient or described by a third party (e.g., by an imaging report, laboratory evaluation, or clinician assessment). As part of a shift toward patient-centered care, there has been an increasing recognition of the importance of measuring and reporting those aspects of health and well-being that are best reported by patients themselves, whether related to disease, treatment, or both. The FDA defines a patient-reported outcome (PRO) as a measurement based on a report that comes directly from the patient (i.e., the study subject) about the status of a patient's health condition, without amendment or interpretation of the patient's response by a clinician or anyone else.³⁴ Over the past 20 years, an expanding body of literature has demonstrated that PROs are associated with traditional outcomes, such as overall survival³⁵⁻⁴⁰ and tumor response.⁴¹ PROs themselves are also increasingly recognized as valid outcomes (e.g., quality of life [QOL], pain, breathlessness, physical functioning).⁴²⁻⁴⁹

Systematic collection of PROs in clinical trials, patient registries, and usual clinical care is feasible and efficient.⁵⁰⁻⁵⁴ PROs are more reflective of underlying health status than physician reporting⁵⁵ and facilitate discussion of important symptoms and QOL with clinicians.⁵⁶ Additionally, they have been shown to serve as supporting documentation, improve symptom management,⁵⁷ and potentially impact clinical decision making.⁵²'⁵⁸ While widespread adoption of PROs as a key component in clinical research has not occurred, there is increasing recognition of their role in complementing traditional clinical and administrative data.⁵⁹ The FDA has identified PROs as the regulatory standard for supporting subjective endpoints, like symptoms, in drug approval and labeling and has provided clear instructions on PRO measurement in drug development trials.³⁴ In addition, FDA has underscored the value and use of PROs in assessing the effects of medical devices in its strategic priorities.⁶⁰

While there are no formal guidelines for inclusion of PROs in registries, PROs contribute information across the spectrum of registry purposes described in Chapter 1, and inclusion of PROs should be considered during the planning and design phases. For example, registries intended to describe the natural history of a disease must include adequate information about symptom burden and related QOL trajectories, especially in the setting of rare diseases, inherited diseases with increasing life span (e.g., cystic fibrosis, sickle cell disease), and heterogeneous diseases (e.g., chronic obstructive pulmonary disease, breast cancer). In registries designed to study effectiveness, patient-reported symptoms can be indicators of adverse consequences of therapy (e.g., toxicity monitoring), targets for meaningful intervention (e.g., symptom control intervention), and means of understanding how patient perceptions of toxicities impact effectiveness (e.g., through adherence behavior). PROs can also serve an important purpose in registries designed for measuring or monitoring safety and measuring quality.

Validated tools should be used to capture PROs whenever possible. Chapters 4 and 5 provides more information on identifying and selecting tools for capturing PROs. Chapter 6 discusses patient-generated data.

Target Population

The target population is the population to which the findings of the registry are meant to apply. It must be defined for two basic reasons. First, the target population serves as the foundation for planning the registry. Second, it also represents a major constituency that will be impacted by the results of the registry.

One of the goals for registry data may be to enable generalization of conclusions from clinical research on narrowly defined populations to broader ones, and therefore the inclusion criteria for most (although not all) registries are relatively broad. As an example, screening criteria for a registry may allow inclusion of elderly patients, patients with multiple comorbidities, patients on multiple therapies, patients who switch treatments during the period of observation, or patients who are using products "off label." The definition of the target population will depend on many factors (e.g., scope and cost), but ultimately will be driven by the purpose of the registry.

As with defining patient outcomes, target population criteria and/or definitions should be consistent with established guidelines and standards within the therapeutic area. Achieving this goal increases the potential utility of the registry by leveraging other data sources (historical or concurrent) with different information on the same target population and enhancing statistical power if similar information is collected on the target population.

In establishing target population criteria, consideration should be given to the feasibility of access to that population. One should try to distinguish the ideal from the real. Some questions to consider in this regard are:

How common is the exposure or disease of interest? Can eligible people be readily identified? Are other sources competing for data on the same patients? Is care centralized or dispersed (e.g., in a referral or tertiary care facility)? How mobile is the target population?

Ultimately, methods to ascertain members of the target population should be carefully considered (e.g., use of screening logs that identify all potential patients and indicate whether they participate and, if not, why not), as should the use of sources outside the registry (e.g., patient groups). Greater accessibility to the target population will reap benefits in terms of enhanced representativeness and statistical power.

Lastly, thought should be given to comparison (control) groups either internal or external to the registry. Again, much of this consideration will be driven by the purpose and specific objectives of the registry. For example, natural history registries do not need controls, but controls are especially desirable for registries created to evaluate comparative effectiveness or safety.

Develop a Study Plan or Protocol

The study plan documents the objectives of the registry and describes how those objectives will be achieved. At a minimum, the study plan should include the registry objectives, the eligibility criteria for participants, and the data collection procedures. Ideally, a full study protocol will be developed to document the objectives, design, participant inclusion/exclusion criteria, outcomes of interest, data to be collected, data collection procedures, governance procedures, and plans for complying with ethical obligations and protecting patient privacy.

In addition to a study plan or protocol, registries may have statistical analysis plans. Chapters 13 and 14 discuss the importance of analysis plans.

Develop a Project Plan

Developing an overall project plan is critically important so that the registry team has a roadmap to guide their collective efforts. Depending on the complexity of the registry project, the project plan may include some or all of the following elements:

Scope management plan to control the scope of the project. It should provide the approach to making changes to the scope through a clearly defined change-control system.

Detailed timeline and schedule management plan to ensure that the project and its deliverables are completed on time.

Cost management plan for keeping project costs within the budget. The cost management plan may provide estimates on cost of labor, purchases and acquisitions, compliance with regulatory requirements, et cetera. This plan should be aligned with the change-control system so that all changes to the scope will be reflected in the cost component of the registry project.

Quality management plan to describe the procedures to be used to test project concepts, ideas, and decisions in the process of building a registry. Having a quality management plan in place can help in detecting design errors early, formulating necessary changes to the scope, and ensuring that the final product meets stakeholders' expectations. The quality management plan should include a clear process for management and disposition of change requests.

Staffing management plan to determine what skills will be needed and when to meet the project goals. (See Chapter 2).

Communication plan that includes who is responsible for communicating information and to whom it should be communicated. Considerations include different categories of information, frequency of communications, and methods of communication. The plan should also provide steps to escalate issues that cannot be resolved on a lower staff level.

Procurement plan for external components or equipment and/or outsourced software development for the planned registry, if pertinent. Such a plan should describe how the procurement process would be managed within the organization. Decisions to procure products or services may have a direct impact on other components of the project plan, including the staffing plan and timeline.

Risk management plan to identify and mitigate risks. Many project risks are predictable events, and therefore they can and should be assessed in the very early stages of registry planning. It is important to prioritize project risks by their potential impact on the specific objectives and to develop an adequate risk response plan for the most significant risks. Some predictable risks include— o Disagreement between stakeholders over the scope of specific tasks. o Inaccurate cost estimates. o Delays in the timeline. o Poor quality or missing data for key variables.

3. Anticipating and Preparing for Changeⁱⁱ

Most, if not all registries, should undergo periodic critical evaluation by key stakeholders to ensure that the objectives are being met. When registry objectives are no longer being met or when clinical or other changes affect the registry (e.g., changes in treatment practices, introduction of a new therapy), the registry may need to be adapted or stop collecting new data.

Many factors may drive the decision to modify an existing registry. For example, a registry may need to transition to a new technology platform to remain functional for its participants, or a registry that was designed to study the natural history of a disease for which there was no effective treatment may change its purpose when a new product or therapy becomes available in the market. Other scenarios in which modifications may be necessary include changes in funding sources and stakeholders or the recognition of potential new regulatory uses (e.g., premarket expansion of indications or safety surveillance) as well as the introduction of new regulatory requirements. (See Case Examples 3 and 4.)

While the considerations for modifying a registry are similar to those for the launch of a new registry, there are several distinguishing features. First, a registry modification is facilitated by an existing registry and the collective experience of conducting that registry. The existing registry can essentially serve as the starting point for creating a prototype of the revision. The planning and design of the registry modification should also benefit from lessons learned in operating the existing version of the registry. What has worked well, and what has been problematic? What challenges have been encountered at every level, from staff entering data at the participating sites to the analyst creating reports? Indeed, one or more of these issues may be contributing factors in the decision to proceed with the changes. Even if this is not the case, the modification provides an opportunity to address these issues. Registry modifications also present unique challenges distinct from the development of a new registry. In particular, transferring data collected in an existing registry to the revised registry (i.e., data migration) can be a complex and resource-intensive process.

Despite these differences, the steps in the execution of a major registry transition are analogous to those involved in planning a new registry. Registries that identify the need for major changes should follow the planning steps outlined in this chapter and the considerations for design and implementation outlined in subsequent chapters of this document.

Registries, particularly those undertaken without a fixed stopping point, may also need to periodically evaluate whether the registry data collection should continue. (See Case Example 2.) Chapter 14 of the third edition of the User's Guide discusses considerations related to stopping registry data collection.

4. Special Considerations

Rare Disease Registriesⁱⁱⁱ

When planning a rare disease registry, special consideration should be given to the role of stakeholders and the possibility for the registry to evolve over time. Stakeholders in a rare disease registry 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. To date, collaboration between stakeholder groups has been critical to the progress made in rare disease 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.⁶¹

Avoiding multiple competing registries in rare diseases is particularly important given the limited number of patients available to be enrolled. This magnifies the role of collaboration. The importance of patient registries in rare diseases and the need to support many organizations has also brought umbrella patient organizations (e.g., National Organization of Rare Disorders [NORD], the Genetic Alliance, EURORDIS) in as stakeholders, as these groups are charged with advising and supporting the development of registries. As with all registries, a single rare disease registry need not fulfill all goals for all potential stakeholders. However, early communication and collaboration with stakeholders can contribute to the development of a registry that provides an infrastructure to support different needs in an efficient way and eliminate barriers to scientific progress.

In developing plans for funding and oversight, registry planners should also consider the possibility for registry modifications. As understanding of the disease improves or as new treatments are developed, the scope of a rare disease registry 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 healthcare providers. (See Case Example 4.)

More information on rare disease registries can be found in Chapter 20 of the third edition of the User's Guide.

Quality Improvement Registriesⁱᵛ

Similar to rare disease registries, early engagement with stakeholders is important for the success of quality improvement (QI) registries. In QI registries, the care provider needs to be engaged and active, as the program is not simply supporting a feedback function or providing a descriptive or analytic function, but is often focused on patient and/or provider behavior change. In many QI registries, these active providers are termed "champions" and are vital for success, particularly early in development.⁶² Once a registry matures, other incentives may drive participation (e.g., recognition, competition, financial rewards, regulatory requirements), but the role of the champion in the early phases cannot be overstated.

A second major difference between planning a QI registry and planning other types of registries is the funding model. QI registries use a wide variety of funding models. For example, a regional or national registry may be funded entirely by fees paid by participating providers or hospitals. Alternately, the registry may supplement participation fees with funding from professional associations, specialty societies, industry, foundations, or government agencies. Some QI registries may not charge a participation fee and may receive all of their funding from other organizations. Local QI registries that operate within a single institution may receive all of their funding from the institution or from research grants. The funding model used by a QI registry largely depends on the goals of the registry and the stakeholders in the specific disease area.

Lastly, change management is an important consideration in planning a QI registry. QI registries need to be nimble in order to adapt to two continual sources of change. First, new evidence comes forward that changes the way care should be managed, and the registry owner must make changes so that the registry is both current and relevant. Second, providers participating in registries manage what they measure, and over time, measures can be rotated in or out of the panel so that attention is focused where it is most critical to overcome a continuing treatment gap or performance deficiency. From a planning standpoint, QI registries should expect ongoing changes to the registry and plan for the resources required to support the changes.

More information on quality improvement registries can be found in Chapter 22 of the third edition of the User's Guide.

5. Resources for Registries

In recent years, registry networks have formed to generate and share knowledge related to registry planning, design, and operations. A registry network is a formal community of organizations operating or using information from patient registries to measure and improve patient health outcomes. Registry networks may be general in nature or focused on specific domains. These networks provide a supportive infrastructure that organizes participants to undertake activities related to the specific goals of the network. Although registry networks may be established for different purposes, at a fundamental level they are strategically collaborative groups where organizations and individuals come together to advance their work, generate and share knowledge, and solve shared challenges. In addition to their knowledge sharing activities, registry networks may build a common infrastructure, create new knowledge, and provide a place to learn about the registries and other registry participants and contributors. Additionally, some registry networks provide access to technical infrastructure such as access to combined datasets or metadata, often facilitated by member registry adoption and use of data standards that the network has developed.

More information on registry networks can be found in 21st Century Registries,²⁰ the eBook addendum to the third edition of the User's Guide.

6. Summary

In summary, planning a patient registry involves several key steps, including articulating its purpose, determining whether it is an appropriate means of addressing the research question, identifying stakeholders, defining the scope and target population, assessing feasibility, and securing funding. A registry team and advisors must be assembled to develop, coordinate, and guide the registry; these individuals should be selected based on their expertise and experience. Governance and oversight for the registry should also be addressed during the planning phase.

While registries differ tremendously in size, scope, and resource requirements, the basic elements of planning described here are relevant for most, if not all registries, and can help to support the launch and operation of a successful registry.

References for Chapter 2

Case Examples for Chapter 2

Case Example 1. Creating a Registry To Fulfill Multiple Purposes and Using a Publications Committee To Review Data Requests

Challenge

Over the past 20 years, there have been significant changes in the treatment of acute myocardial infarction (AMI) patients. Evidence from large clinical trials has led to the introduction of new guidelines and therapies for treating AMI patients, including fibrinolytic therapy and percutaneous coronary intervention. While these treatments can improve both morbidity and mortality for AMI patients, they are time sensitive and must be administered very soon after hospital arrival in order to be most effective.

After the release of its first fibrinolytic therapy product in 1987, the sponsor's field representatives learned from their discussions with emergency department physicians, cardiologists, and hospital staff that most clinicians believed they were treating patients quickly, although there was no documentation or benchmarking to confirm this assumption or to identify and correct delays. At that time, many emergency departments did not have readily available diagnostic tools (such as angiography labs), and hospitals with AMI-specific decision pathways and treatment protocols were the exception rather than the rule.

In addition, since fibrinolytic therapy was being widely used for the first time, the sponsor wanted to gather safety information related to its use in real-world situations and in a broader range of patients than those treated in the controlled environment of a clinical trial.

Proposed Solution

The sponsor decided to create the registry to fulfill the multiple purposes of identifying treatment patterns, promoting time-to-treatment and other quality improvements, and gathering real-world safety data. The scope of the data collection necessary to meet these needs could have made such a registry impracticable, so the project team faced the sizable challenge of balancing the data needs with the feasibility of the registry.

The sponsor formed a scientific advisory board with members representing the various clinical stakeholders (emergency department, cardiology, nursing, research, etc.). The scientific advisory board developed the dataset for the registry, keeping a few guiding principles in mind. These principles emphasized maintaining balance between the clinical research and the feasibility of the registry. The first principle was to determine whether the proposed data element was necessary by asking several key questions: How will the data element be used in generating hospital feedback reports or research analyses? Is the data element already collected? If not, should it be collected? If it should be collected, is it feasible to collect those data? The second principle focused on using existing data standards whenever possible. If a data standard did not exist, the team tried to collect the data in the simplest possible way. The third principle emphasized data consistency and making the registry user-friendly by continually refining data element definitions until they were as clear as possible.

In 1990, the sponsor launched the registry. During the 16 years that the registry was conducted, it demonstrated that the advisory board's efforts to create a feasible multipurpose registry were successful. The registry collected data on the clinical presentation, treatment, and outcomes of over 2.5 million patients with AMI from more than 2,150 participating sites.

The success of the registry presented a new challenge for the registry team. The sponsor received a large volume of requests to analyze the registry data, often for research topics that fell outside of the standardized reports developed for the registry. As a guiding principle, the registry team was committed to making the data available for research projects, but it had limited resources. To support these requests, the team developed a process that would allow outside researchers to access the registry data without overburdening the registry team.

The registry team created a publication process to determine when another group could use the data for research. The team set high-level criteria for all data requests: the analysis had to be feasible given the data in the registry, and the request could not represent a duplication of another research effort.

The registry team involved its scientific advisory board, made up of cardiologists, emergency department physicians, nurses, research scientists, pharmacists, and reviewers with specialties in biostatistics and statistical programming, in creating a publication review committee. The review committee evaluated all research proposals to determine originality, interest to peers, feasibility, appropriateness, and priority. The review committee limited its review of research proposals to a set number of reviews per year, and scheduled the reviews and deadlines around the abstract deadlines for the major cardiology conferences. Research analyses had to be intended to result in peer-reviewed presentations and publications. Researchers were asked to submit proposals that included well defined questions and an analysis plan. If the proposal was accepted, the researchers discussed any further details with the biostatisticians and statistical programmers who performed the analyses (and who were employed at an independent clinical research organization). The results were sent directly to the researchers.

The scientific advisory board and review committee remained involved in the process after a data request had been granted. All authors submitted their abstracts to the review committee before sending them to conferences. The review committee offered constructive criticism to help the authors improve their abstracts. The review committee also reviewed manuscripts before journal submission to help identify any issues or concerns that the authors should address.

Results

This publication process enabled the wealth of data collected in this registry to be used in over 150 scientific abstracts and 100 peer-reviewed articles, addressing each of the purposes of the registry as well as other research topics. By involving the scientific advisory board and providing independent biostatistical support, the registry team developed an infrastructure that enhanced the credibility of the research uses of this observational database.

Key Point

Registries can be developed to fulfill more than one purpose, but this added complexity requires careful planning to ensure that the final registry data collection burden and procedures are feasible. Making sure that the advisory board includes representatives with clinical and operational perspectives can help the board to maintain its focus on feasibility. As a registry database gains large amounts of data, the registry team will likely receive research proposals from groups interested in using the data. The registry team may want to set up a publication process during the registry design phase.

For More Information

Califf RM. The benefits of moving quality to a national level. Am Heart J. 2008;156(6):1019–22. PMID: 19032994. DOI: 10.1016/j.ahj.2008.09.005.

Rogers WJ, Frederick PD, Stoehr E, et al. NRMI Investigators. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the NRMI from 1990 to 2006. Am Heart J. 2008;156(6):1026–34. PMID: 19032996. DOI: 10.1016/j.ahj.2008.07.030.

Gibson CM, Pride YB, Frederick PD, et al. NRMI Investigators. Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the NRMI from 1990 to 2006. Am Heart J. 2008;156(6):1035–44. PMID: 19032997. DOI: 10.1016/j.ahj.2008.07.029.

Peterson ED, Shah BR, Parsons L, et al. NRMI Investigators. Trends in quality of care for patients with acute myocardial infarction in the NRMI from 1990 to 2006. Am Heart J. 2008;156(6):1045–55. PMID: 19032998. DOI: 10.1016/j.ahj.2008.07.028.

Case Example 2. Determining When To Stop an Open-Ended Registry

Challenge

Bupropion, an antidepressant with the potential for prenatal exposure, was labeled with a pregnancy category C by the U.S. Food and Drug Administration (FDA) due to prior animal data. The manufacturer established a prospective pregnancy registry to monitor pregnancy exposures to bupropion for any potential increased risk of congenital anomalies. Because the purpose of the registry was postmarketing safety surveillance, the duration of the registry was open ended. The registry had collected data on more than 1,500 exposed pregnant women over 10 years when a potential signal suggestive of a bupropion-related increase in cardiovascular birth defects emerged.

Proposed Solution

The advisory committee reviewed the registry data to assess the potential signal. However, due to the potential bias from the large percentage of cases lost to followup (35.8%), retrospective reports, and incomplete descriptions of the reported cardiovascular defects, it was not possible to determine the credibility of the potential signal using registry data alone. Further, the sample size was not adequate to reach definitive conclusions regarding the absolute or relative risk of any specific birth defects in women using bupropion during pregnancy (as the registry was powered only to examine the rate of birth defects overall) and was unlikely to achieve its goal as structured.

The advisory committee recommended a study to expedite the accumulation of pregnancy outcome data among women exposed to bupropion during pregnancy. In response, a large, claims-based, retrospective cohort study was conducted. This study enrolled 1,213 women exposed in the first trimester and did not confirm a consistent pattern of defects (Cole et al., 2007). The prevalence of cardiovascular defects associated with first-trimester exposure to bupropion was 10.7 per 1,000 infants.

Results

The advisory committee reviewed the evidence and concluded that the signal did not represent an increased risk. The committee recommended discontinuation of the registry based on findings from the retrospective cohort and 10 years of surveillance through the registry. The committee took the position that sufficient information had accumulated to meet the scientific objective of the registry. The high lost-to-followup rate was also taken into consideration. The registry closed to new enrollments on November 1, 2007, and continued to follow existing cases through March 31, 2008.

Key Point

In a registry without a specified end date or target size, it is important to periodically review the registry data to determine if the registry has met its scientific objectives and to ensure that the registry purpose is still relevant.

For More Information

Cole JA, Modell JG, Haight BR, et al. Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol Drug Safety. 2007;16(5):474–84. PMID: 16897811. DOI: 10.1002/pds.1296.

The Bupropion Pregnancy Registry. Final Report: September 1, 1997–March 31, 2008. Issued August 2008. http://pregnancyregistry.gsk.com/bupropion.html. Accessed June 10, 2019.

Alwan S, Reefhuis J, Botto LD, et al. Maternal use of bupropion and risk for congenital heart defects. Am J Obstet Gynecol. 2010;203(1):52.e1–6. Epub 2010 Apr 24. PMID: 20417496. DOI: 10.1016/j.ajog.2010.02.015.

Thyagarajan V, Robin Clifford C, Wurst KE, et al. Bupropion therapy in pregnancy and the occurrence of cardiovascular malformations in infants. Pharmacoepidemiol Drug Safety. 2012;21(11):1240–42. PMID: 23109236. DOI: 10.1002/pds.3271.

Case Example 3. Modifying a Registry Due to Changes in Standards of Care

Challenge

When it was launched in 2007, the 5-year GOLD reGISTry enrolled only patients with advanced gastrointestinal stromal tumors (GIST). This population was of interest to researchers because standards of care for advanced GIST were not as clearly defined and widely used as the standard of care for localized GIST, which was complete surgical excision. The sponsor expected that the outcomes data collected from advanced GIST patients would be valuable in helping to refine standards of care for these patients.

In 2008 and 2009, Gleevec®/Glivec® (imatinib mesylate) received FDA and European Medicines Agency (EMA) approval for adjuvant use in localized GIST after tumor resection. This approval, combined with emerging clinical trial data, prompted new interest in collecting diagnostic, treatment, and outcomes information from patients with localized GIST.

Proposed Solution

The sponsor had selected a steering committee with engaged key opinion leaders who provided guidance for the study and encouraged flexibility in study design to allow for potential changes. In 2009, the steering committee convened and determined that the registry would begin collecting data on patients with localized GIST, in addition to those with advanced disease who were already enrolled in the registry. The study team drafted a protocol amendment to include the localized GIST population and allowing assessment of physician adherence to new clinical guidelines published by the European Society of Medical Oncology the same year. The data management and statistical analysis plans were also revised to allow for the incorporation of the new data.

Significant efforts were then directed at site engagement, including abstract submissions and publicity through the key opinion leaders. The registry also maintained site interest through interim study summaries presented at professional congresses. The sponsor had limited monitoring resources available to accommodate the new patient population, so study designers developed a plan that used remote monitoring and training, reserving onsite visits for research-naïve sites or for-cause audits. This allowed monitors to focus on those sites that required more training and allowed these sites to gain clinical research experience in an observational study.

Results

The registry enrolled 1,632 patients in the two populations within four years: more than 1,000 with advanced GIST, and more than 500 with localized GIST. The registry provided a large dataset on treatment and long-term outcomes for patients with GIST in the real-world setting. The steering committee played an important role in the recruitment and retention of sites, highlighting the importance of the study through publications and interim summaries presented at scientific and professional congresses throughout the enrollment period.

Key Point

Changes in standard of care can significantly impact the design of a study as new treatments are approved or new patient populations become of interest. Registry developers should anticipate that such changes might occur, and should consider what aspects of the registry could be most impacted. A steering committee well regarded in the field and knowledgeable about the disease and treatment can provide significant guidance during registry transitions and keep sites engaged as the changes are implemented.

For More Information

Barrios CH, Blackstein ME, Blay JY, et al. The GOLD ReGISTry: a Global, Prospective, Observational Registry Collecting Longitudinal Data on Patients with Advanced and Localised Gastrointestinal Stromal Tumours. Eur J Cancer. 2015;51(16):2423-33. PMID: 26248685. DOI: 10.1016/j.ejca.2015.07.010.

Chacon M, Reichardt P, Gu J, et al. The GOLD reGISTry: A global observational registry collecting longitudinal data on patients with advanced GIST—Second annual summary. J Clin Oncol (Meeting Abstracts). 2010 May;28(15 Suppl.):10092.

Case Example 4. Using Registries To Understand Rare Diseases

Challenge

Rare diseases pose special and unique research challenges. The small number of affected patients often results in limited clinical experience within individual healthcare 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.

Results

The registry has longitudinal data on more than 12,000 patients from more than 700 healthcare 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, healthcare 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 dataset. 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 healthcare 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. PMID: 12133749. DOI: 10.1016/s0002-9343(02)01150-6.

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. PMID: 19732054. DOI: 10.1111/j.1365-2141.2009.07872.x.

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. PMID: 20084461. DOI: 10.1007/s10545-009-9009-6.

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. PMID: 18979180. DOI: 10.1007/s10545-008-0868-z.