Patient registries in the field of rare diseases
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April 2009 Update June 2011 PATIENT REGISTRIES IN THE FIELD OF RARE DISEASES
Overview of the issues surrounding the establishment, management, governance and financing of academic registries
RDTF Report on patient registries in the field of rare diseases (June 2011)
2 Table of contents Introduction 3 Part I 5 Definition of a patient registry (PR)
5 Purposes of patient registries in the field of rare disease
Typology of data collections, other than registries
8 Status of data collections
9 Points to consider when planning a patient registry in the field of rare diseases
Steps to consider when developing a PR in the field of RD
12 Part II 15 Ethical and legal issues
15 Consent requirement
Protection of patient privacy
Transparency, oversight and ownership
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Bibliography
19 Annex 1: List of workshop participants and contributions
Annex 2: List of rare disease registries in Europe
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RDTF Report on patient registries in the field of rare diseases (June 2011)
3 Introduction
Patient registries and databases constitute key instruments for the development of clinical research in the field of rare diseases (RD), and the improvement of patient care and healthcare planning as well as social, economical and quality of life outcomes. They are the appropriate way to pool scarce data without bias for epidemiological and/or clinical research. They are vital to assess the feasibility of clinical trials, to facilitate the planning of appropriate clinical trials and to support the enrolment of patients and to assess the impact of new interventions.
Registries of patients treated with orphan drugs are particularly relevant as they allow the gathering of evidence on the effectiveness of the treatment and on its possible side effects, keeping in mind that marketing authorisation is usually granted at a time when evidence is still limited although already somewhat convincing.
When established, databases should be maintained and their use optimised through exchange of data between interested parties. However, the status of such databases is not well defined and most institutions have no written policies or agreements regarding this activity.
Regulations concerning registries are in early stages in most European countries and, with the multiplicity of actors and of rules at MS level, the situation is difficult to comprehend. No guidelines are available yet on best practices for exchanging and sharing data. The notion of return of benefits to research subjects/communities is fairly recent.
Databases are expensive to establish and maintain. They require the cooperation of many healthcare providers and require careful management. PR should only be established when financial resources and expertise are present to support them. Furthermore, PR systems tend to have added value if the disease in question has a good prospect for intervention, control, prevention and for research that can lead to these ends.
They are of high interest to researchers, industrial partners, healthcare professionals, patients and patient organisations, and, ultimately, for the community. It is difficult to separate research conducted by the non-profit and for-profit sectors, as researchers from both sectors are often involved in the same projects. Whilst this enables effective technology transfer, it also gives rise to concerns about conflicts of interest. There is a need to promote confidence in research based on data collections.
Patient registries have been in place for several decades in sectors such as cancer, birth defects and cardiovascular diseases. This long and broad history of data collection is the basis on which to build guidelines for registration of patients with a RD although RD patient registries have some additional features which make them specific:
the scarcity of cases and the complexity of these diseases imposes a large geographical coverage of the data collection which implies multiple collaborations and exchanges of data, usually trans-national; RDTF Report on patient registries in the field of rare diseases (June 2011)
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most RD are genetic in origin and a large proportion of them may have one family member affected, which implies that it is desirable that family related cases be traceable;
the cost of establishing and maintaining a PR is nearly equal for a common disease as it is for a RD, although budgets are more difficult to obtain for the latter.
The European Commission, in its Communication: “Rare diseases: Europe’s challenge” emphasizes the strategic importance of PR in the field RD.
providing that these resources are accessible through agreed upon rules. Many research and public health networks financially supported by DG RTD and by DG SANCO have put in place such shared infrastructures, which have been proven to be very efficient tools in improving knowledge and organising clinical trials.”
including development of strategies and tools for periodical monitoring of the quality of databases and for database upkeep; a minimum common set of data to be collected for epidemiological and public health purposes; attention to user-friendliness, transparency and connectivity of databases; intellectual property, communication between databases/registries (genetic, more generically diagnostic, clinical, surveillance-driven, etc). Importance should be given to linking international (European) databases to national and/or regional databases, when existing.”
To discuss these issues and produce recommendations from a health professional’s perspective, the Rare Diseases Task Force organised a workshop on 13 March 2008 in Paris, France, to which 23 experts (see Annex 1) from 10 European countries were invited. This document was finalised as an output of this workshop where a preliminary version was presented and discussed.
The present document is based on a compilation of several previously published documents which are listed at the end of the report. An updated 1 list of patient registries in Europe in the Orphanet Report Series is also provided in Annex 2. The report and annex has been updated in June 2011 by the Scientific Secretariat of the European Union Committee of Experts on Rare Diseases (EUCERD).
This document forms part of a project financed by the European Commission, DG Sanco (Scientific Secretariat of the Rare Disease Task Force Contract n° 2004105).
1 Updated in January 2011. RDTF Report on patient registries in the field of rare diseases (June 2011)
5 Part I Definition of Patient Registry (PR)
The WHO definition of “patient registry” is “a file of documents containing uniform information about individual persons, collected in a systematic and comprehensive way, in order to serve a pre-determined scientific, clinical or policy purpose 2 ”. It does not pre-judge the amount of collected data which can be minimal or extensive, but implies continuity, as distinct from a cross-sectional survey.
The US National Committee on Vital and Health Statistics 3 defines registries as “an organized system for the collection, storage, retrieval, analysis, and dissemination of information on individual persons who have either a particular disease, a condition (e.g., a risk factor) that predisposes (them) to the occurrence of a health-related event, or prior exposure to substances (or circumstances) known or suspected to cause adverse health effects”.
In its most simple form, a PR consists of a collection of paper cards kept inside a “shoe box” by physicians. Nowadays PR are collections of computerised data.
It is usual to distinguish between population-based registers, which refer to a geographically defined population and aim to register all cases in that population, and registers based on clinical centres or other criteria where the population coverage may not be clear. These two types of register have different uses. It may also be useful to distinguish exhaustive and non- exhaustive registers (the latter are possibly not registers by some definitions) - an exhaustive register seeks to include ALL cases which fulfil the inclusion criteria. Non-exhaustive registers (or databases) can however be very useful for finding patients for clinical research for example.
Purposes of PR in the field of RD
PR can be established to monitor incidence or prevalence, especially in relation to early warning of increases. Where incidence/prevalence is expected to be stable over long periods, an ad hoc study may be more cost-effective. However, for rare diseases a register and ad hoc study are often effectively the same, as a relatively long period of time is needed
2 Brooke EM. The current and future use of registers in health information systems. Geneva: World Health Organization; 1974. Publication No. 8. 3
Available at: Frequently Asked Questions about Medical and Public Health Registries. The National Committee on Vital and Health Statistics http://ncvhs.hhs.gov/9701138b.htm. Accessed April 2009.
RDTF Report on patient registries in the field of rare diseases (June 2011)
6 to establish a precise incidence/prevalence, and to look for differences between populations if relevant.
Establishing natural history
The straightforward purpose of patient registries is to document the natural history of the disease, meaning its characteristics, management and outcomes with or without treatment. For rare diseases of genetic origin, the purpose may also be to establish a genotype- phenotype correlation. The natural history may be variable from one population group to another and usually changes over time, especially if a new therapy becomes available. The best example is the change in survival of patients with lysosomal storage diseases since the introduction of enzyme replacement therapies. Registries need to keep pace with the ever changing complexity of clinical factors in rare diseases especially in the context of increased life expectancy and ageing.
Registries have been often created in the past to monitor safety. In that context registries serve as an active surveillance system for the occurrence of unexpected or harmful events for products or interventions in general and in particular for drugs used off-label, which is the case for most drugs used by patients living with a rare disease. In the context of orphan drugs or new medical or surgical intervention, it is likely to be a necessary step as usually little is known at the time the intervention is implemented, and certainly not enough to be sure that any adverse effects have been properly assessed.
However registries to monitor safety are of limited interest for uses other than safety monitoring as they only monitor treated cases which may be a minority of cases or a skewed sample of cases. Usually they are product registries rather than disease registries. If there is more than one product from two different manufacturers for a given disease, this will lead to the establishment of two separate product registries with limited value, which will not allow the comparison of outcomes with each of the products.
Registries can also be established to provide data for assessing the clinical effectiveness or the cost-effectiveness of new interventions in a real-world setting. This is required because the clinical studies performed to assess the clinical efficacy of new treatments are based on studies of selected patients following an “ideal protocol”, which differ from the clinical practice afterwards when the treatment is implemented in the healthcare setting. This is why more and more regulatory authorities and healthcare insurers request that a registry be implemented when an orphan drug receives a marketing authorisation. This type of registry is much more interesting than the previous type as it includes all patients, not only the treated patients. However, registries have to be designed specifically to assess cost- effectiveness in order to accomplish this purpose even if cost-effectiveness may be difficult to assess in rare diseases.
RDTF Report on patient registries in the field of rare diseases (June 2011)
7 Measuring quality of care / plan services Registries may also be established to measure the quality of care. It is usually compared to standards which have been established and which are considered as “gold standards”. The IOM definition for quality of care is “the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge”. This type of registry is useful to identify disparities between health care outcomes and provide evidence for improving them. It is very interesting in a European context as health care systems, as well as attention given to patients with rare diseases, are very diverse. It is also useful for healthcare planning and gold standards exist only for a very limited number of rare diseases. With regard to quality of care self-reporting PR can complement reports from physicians and cover issues such as quality of life and social issues.
PR are also the basis for research into causes when not firmly established, providing that the potential causal factors are registered as well.
In the field of rare diseases, a reason for establishing a patient registry is also to collect enough data on a given disease to make it visible and to motivate researchers and Industry to work on it. It seems to be an effective approach, providing that the registry is designed properly to generate useful information.
Another reason is to have an inventory of patients to re-contact for participation in epidemiological studies, clinical trials or for Health Technology Assessment to monitor real access to treatments. In that case the data needed on each patient is limited to the diagnosis and the contact details. It should be better named a “contact list” rather than a PR.
Yet another reason to make key data, such as genetic status, diagnostic criteria etc, available to research groups, is to reduce the repetitive collection of the same data thereby reducing demands on participants and their carers.
Of course most registries have the ambition to serve more than one purpose, although it is not always possible. Sticking to selected purposes requires a lot of attention in the design phase. It is common to mix up goals such as management of patients and management of data for research purpose. It is desirable for the format of data to be compatible between these two types of data registration systems to allow extraction, but the other aspects are too different to be accommodated by one system. Another common mistake is for registries to accept to collect data which they cannot successfully access, which can potentially paralyse the project.
RDTF Report on patient registries in the field of rare diseases (June 2011)
8 Typology of data collections, other than registries Registries are only one specific type of data collection. Several other types of data collection exist with their own merit and limit. They are reviewed below with reference to their particular type of use.
These are computerised hospital files where the patient diagnosis is coded using a defined nomenclature, usually the International Classification of Diseases (ICD) developed by WHO. They are clinical tools, adapted to counting patients using specific types of healthcare services. They are used by healthcare managers. They are not designed for research purposes although they may sometimes be used for research purposes. Other sources can also be used such as death certificates or health insurance data. In the field of rare diseases their use is limited as the ICD does not yet provide specific codes for more than 240 RD. This should change with the release of ICD 11, and if these systems were perfect and if ICD coding for RD were perfect, much of the data we need would be available from health system data.
These are defined as permanent registrations of patient information in a systematic way, carried out by healthcare providers on the basis of their referrals. It is a passive ongoing registration activity. The advantage of such a system is its low cost, as there is no cost attached to the identification of cases, as they are referred through the healthcare system. The limits of this approach include the fact that registered cases are not a true representation of the general population but rather a biased sample, usually biased towards more severe cases or cases from higher socio-economic classes. If the data collection is done properly, the data set may be of interest for some research purposes, but not suitable for epidemiologic studies, unless it can be established that all the cases are referred to the collecting centre. Observatories of cases are also called hospital registries.
This type of data collection is targeted at offering the possibility to answer one or more specific research questions. This is one shot data gathering, which may be repeated in at another time. The data collected is in the exact format required for the anticipated analysis. The protocol of the study is designed to ensure a clear answer to the research question(s). This implies an adequate definition of the sampled population, an adequate size of the sampled population, and an adequate management of the study to minimise the number of non-responders.
The ad hoc study is the most efficient instrument for research purposes as their protocol is well adapted to the research needs (the sample is fully representative and thus the results are conclusive) and the cost of the study is much lower that any type of permanent data collection, as the study takes place during a limited period of time. Ad hoc studies are flexible instruments with protocols adapted to the most recent discoveries about a disease.
There are several types of ad hoc studies, namely clinical trials, prospective cohorts, retrospective cohorts, case-control studies, cross-sectional (prevalence) studies, etc. RDTF Report on patient registries in the field of rare diseases (June 2011)
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Ad hoc studies can be used in combination with longer term registries to answer specific research questions
In the context of a registry, the data collection can be transversal (all defined patients are registered once) or longitudinal (data is collected at different points in time for the same patient). If there is a systematic follow-up protocol, the dataset is defined as a cohort. For rare disease clinical research, cohorts are highly desirable as they are usually the only way to collect enough data to allow a proper analysis, due to the very small number of cases. Status of data collections
There are several types of data collections: In “anonymous” data collections the data is originally collected without identifiers and is impossible to link to their sources. This type of data collection is adequate for incidence and prevalence studies for instance, but is less appropriate for clinical research. The advantage of this technique is to maximise data protection and to ease the collaboration between researchers.
In “anonymised” data collections, data is originally identified, but is then irreversibly stripped of all identifiers and are impossible to link to their sources.
In “indirectly identifiable” data collections, data is unidentified for research purposes, but can be linked to their sources through the use of a code. This is the most common type of data collected for clinical research.
In “directly identifiable” data collections, identifiers, such as a name, patient number, or clear pedigree location, are attached to the data. This is, for example, the case for hospital files. The use of this type of data is regulated by strict rules in most, if not all, countries. Rules concerning this type of data collection differ from one country to another.
It is important that the degree of anonymity of the data is made clear to patients at the time of consent as uncertainty in this area is becoming more and more of a barrier to participation.
RDTF Report on patient registries in the field of rare diseases (June 2011)
10 Points to consider when planning a patient registry in the field of rare diseases
The initial steps in planning a registry should consider the following points:
“Articulating the purpose and the objectives of the registry” A clearly defined purpose helps clarify the need for certain data, including their scope and level of details. It prevents collecting large amount of data of limited value for the targeted objectives.
“Determining if the data being sought has already been collected elsewhere, totally or Yüklə 0,55 Mb. Dostları ilə paylaş:
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