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Keywords:

  • Clinical trial;
  • German Clinical Trials Register;
  • Germany;
  • register;
  • trial registry

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Situation in Germany and the main goals of the German Clinical Trials Register
  5. Implementing the German Clinical Trials Register
  6. Conclusion
  7. Acknowledgement
  8. References

Objective It is a moral responsibility towards patients, funding organizations, the scientific community and the general public to publish not only the results of clinical trials but also to inform prospectively about planned trials. This is especially important for scientists, funding organizations, and ethics committees, since they are involved in the planning of new trials, which should rely on the knowledge of existing trials. Moreover, patients can only participate in clinical trials if they or their physicians are aware of ongoing trials for which they are eligible. In order to provide a central portal for information on clinical research in Germany and to facilitate the search for specific trials, the German Clinical Trials Register was implemented in 2008.

Method An internet-based prototype of the German Clinical Trials Register was developed in close co-operation with the World Health Organization's registries network on the basis of the internationally harmonized data specification. This was further adapted to a bilingual registry's needs. Co-operation with medical ethics committees in Germany has been initiated with the aim of a joint synergistic data acquisition procedure.

Results The German Clinical Trials Register was launched in August 2008. It was approved as the World Health Organization's primary registry for Germany in October 2008, and fulfils the requirements of the International Committee of Journal Editors.

Conclusion The German Clinical Trials Register provides a central bilingual portal for all users (including scientists, patients, physicians, funding organizations, and ethics committees) for information on planned, ongoing, and completed clinical trials conducted in Germany. The German Clinical Trials Register allows International Committee of Journal Editors and World Health Organization-compliant registration of clinical trials in Germany.

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Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Situation in Germany and the main goals of the German Clinical Trials Register
  5. Implementing the German Clinical Trials Register
  6. Conclusion
  7. Acknowledgement
  8. References

Decisions in healthcare and especially in the treatment of patients as well as the planning of medical research should be based on evidence which can ideally be drawn from the results of controlled and randomized clinical trials. A significant proportion of clinical trials is, however, never published (1–3). It has been demonstrated that trials with a statistically significant result are more quickly published and more likely to be published at all than those with null or negative results (4). Moreover, important discrepancies between sample size calculations, statistical analyses, and primary outcomes as defined in trial protocols or other documents compiled in the planning of a trial and those eventually reported have been observed (5–8). This is especially alarming since these trial characteristics have an important impact on the interpretation and conclusions of randomized trials. Both publication bias and outcome reporting bias can lead to a significantly distorted assessment of an intervention: benefits are usually overestimated, whereas potential harms are underestimated. As a consequence, patients may not be treated optimally.

Comprehensive, publicly accessible clinical trial registries are a widely accepted tool to fill the information gap (9–13). In informing the public and especially patients about planned, ongoing, and completed trials, clinical trial registries fulfill an ethical requirement towards patients included in trials. Volunteers participating in clinical trials expect that they serve the community by contributing to medical knowledge. This implies that results of those trials have to be made public. In addition, physicians and their patients need to know about suitable trials for participation. Trial registries facilitate co-operation and the saving of resources. Clinical trial registries can be regarded as a first step towards transparency in clinical research.

In 2004 the International Committee of Medical Journal Editors (ICMJE) pushed forward clinical trial registration by demanding that from 2005 onwards, every clinical trial has to be prospectively registered as a prerequisite for the publication of its results (14). The ICMJE accepts registration of clinical trials in any primary registry approved by the World Health Organization (WHO) (15).

To date several organizations and institutions including the World Medical Association, the European Science Foundation, and the US Food and Drug Administration require prospective registration of all clinical trials in which human participants are prospectively assigned to one or more health-related interventions to evaluate the effects on health outcomes (16–18). The WHO, with its international clinical trials registry platform (ICTRP), co-ordinates existing registries worldwide and has taken the lead in establishing minimum standards and operating procedures for so-called primary registries (19). Moreover, a trial registration dataset has been developed, which would be used by all primary registries for data transfer to the ICTRP search portal. The central search portal, which was launched in 2007 by the WHO, aims to provide a ‘one-stop shop’ to search for reliable clinical trials information worldwide (20).

Situation in Germany and the main goals of the German Clinical Trials Register

  1. Top of page
  2. Abstract
  3. Introduction
  4. Situation in Germany and the main goals of the German Clinical Trials Register
  5. Implementing the German Clinical Trials Register
  6. Conclusion
  7. Acknowledgement
  8. References

Germany, with more than 80 million inhabitants, 35 University Medical Centers, and its pharmaceutical industry is an important location for clinical research. Fifty-three medical ethics committees review all clinical trials conducted in Germany. Both institutional review boards and competent authorities publish yearly statistics and surveys on the number of clinical trials in Germany, along with some information on their characteristics. However, the available information is incomplete. Results of German clinical research projects are largely underreported (21). Competent authorities can only report on drug trials and the information publicly available is limited to very basic trial characteristics. A prospective, complete, and detailed overview on the number and type of clinical trials conducted in Germany is lacking. Therefore, different stakeholders asked for a central publicly accessible portal to collect and provide this information. Initial discussions on clinical trial registration in Germany began in 2000 and led to the formation of a widely supported interdisciplinary initiatives group that called for a national clinical trials register in 2005. The following main goals for the German clinical trials register have been defined:

  • • 
    provide a complete, up-to-date overview of clinical trials conducted in Germany;
  • • 
    allow easy-to-use and free-of-charge access for all users;
  • • 
    provide a unique access point to current trials in Germany;
  • • 
    inform the public about ongoing trials in German and English languages;
  • • 
    provide the basis for scientific analysis of clinical research in Germany;
  • • 
    enhance quality and transparency of medical research in Germany;
  • • 
    allow sponsors to search for related trials when planning a new clinical trial;
  • • 
    enhance the acceptance of clinical trials in the German population; and
  • • 
    represent German experiences, perspectives, and interests in the international registry network.

Various different user groups will have a potential benefit from a German clinical trials registry. Patients and their physicians will have a central portal for information on all trials, especially those ongoing trials which might be suitable for their participation. Recruitment for trials can thus be facilitated. Clinical researchers are encouraged to co-operate with their colleagues, and networking between different research groups in Germany and beyond is supported. Unnecessary duplication of research can be avoided when organizations such as ethics committees and funding organizations are able to get a complete picture of planned, ongoing, and completed trials in Germany. The German Clinical Trials Register will allow for the first time a comprehensive analysis of the clinical research situation in Germany. Neglected clinical research areas as well as competence centres of expertise in clinical research or specific diseases can be identified. These figures may serve as a valid basis for future funding and conduct of clinical research in Germany.

Patients and their physicians often ask for trial information in the German language. Only by providing information in German can patients, their doctors, and the public be informed properly. Greater acceptance of clinical research in Germany can only be reached if valid up-to-date and complete information on all clinical trials is displayed in the register in the local language. Co-operation between different stakeholders in the Germany-wide network of clinical research can only be formed and enhanced by knowing the situation and the key players in Germany. This has been a strong argument for the implementation of a German clinical trials register.

Implementing the German Clinical Trials Register

  1. Top of page
  2. Abstract
  3. Introduction
  4. Situation in Germany and the main goals of the German Clinical Trials Register
  5. Implementing the German Clinical Trials Register
  6. Conclusion
  7. Acknowledgement
  8. References

The benefits of a national register were also seen by the Federal Ministry of Research and Education, which decided to fund the project for the first four years. After an international review process the University Medical Center Freiburg was selected in 2007 to implement and run the German Clinical Trials Register (GermanCTR). It is a joint project of the Clinical Trials Center Freiburg and the German Cochrane Center and is conducted under the lead of Professor Martin Schumacher at the Department of Medical Biometry and Statistics. The GermanCTR is supported by a guidance and advisory board whose members represent different stakeholders and help to improve and promote the register in their different fields.

Based on the experience with two other registries maintained at the Clinical Trials Center Freiburg [the method-specific DeReG (22, 23) and the local registry of the University Medical Center Freiburg (24)], a first prototype of the GermanCTR was developed to meet all the WHO criteria for a primary registry. The prototype was launched in August 2008 and approved by the WHO in October 2008 (25, 26). In mid-2009 the prototype software will be replaced by a new software solution, the development of which has been outsourced to an information technology company. This new software is being designed specifically to meet the needs of the data management staff as well as to increase usability for data providers and users of the registry website.

Specifying the dataset to allow statistical analysis and facilitate bilingual maintenance

The GermanCTR aims to collect most information in a coded form using existing international coding systems such as ICD-10, MeSH, or MedDRA where possible, and also provide bilingual catalogs and selection lists. When entering trial information the user needs to complete these coded parameters in one language only, whereas remaining free-text parameters such as the title of the trial require entry in both English and German. Quality of the data can be improved since coding allows the definition and implementation of automatic plausibility and validity checks. Moreover, coding of the data enables the GermanCTR to provide valid descriptive statistics and analysis across all trials.

In addition, the WHO dataset (27) was expanded for the GermanCTR. New parameters like ‘Corresponding laws’ were introduced in order to meet the demands of different user groups in Germany such as ethics committees and funding organizations.

Further challenges in the development of the GermanCTR

The major challenge facing the GermanCTR is to reach completeness and to avoid unnecessary work for investigators or sponsors, and trialists. The aim is to build up synergies when entering trial information into different systems; for example, approval documents, regulatory databases, and registries. Since clinical trial registration is voluntary in Germany, several data acquisition strategies are followed. One is co-operation with existing specialized or local trial registries in Germany and, as a next step, with international registries like http://www.clinicaltrials.gov that are already accepting data from German trials. Different data transfer strategies are possible between the so-called partner registries in Germany: either a bottom-up dataflow from the partner registry to GermanCTR or top-down from the primary to the partner registry.

To reach completeness the GermanCTR seeks to combine the application procedure at ethics committees with the trial registration process. Extra work for applicants will thus be minimized. The board of the working group of medical ethics committees in Germany supports the GermanCTR. A close collaboration between the ethics committee's working groups database taskforce and the GermanCTR has been established, and a joint online data entry platform is planned. The advantage of collaboration with the ethics committees is that all clinical trials have to be approved. Ethics committees in Germany receive applications for all clinical trials and studies, not only trials that meet the WHO definition of an interventional trial (19).

Information on observational and epidemiological studies is valuable clinical research information. Some biomedical journals already ask for prospective registration of these studies as well. Especially in orphan diseases, there is a need to distribute information on all types of medical research including observational and epidemiological studies to support better recruitment of patients with rare diseases and to allow the assessment of potential benefits or harms of (new) orphan drugs and treatments. That is why the GermanCTR sees it as its responsibility to also provide information on these studies. Currently the same dataset as for interventional trials is used.

Next steps

The main objective for the future is to promote clinical trial registration and the use of the GermanCTR on a large scale, in order to establish the register as a routine tool in medical research and health care. A promotion strategy for 2009 has already been developed including presentations at large medical congresses in Germany, and publication in German medical journals and other print media. Further steps will expand the network of partner registries and to push forward the co-operation with the ethics committees on local as well as national levels.

As the WHO primary registry for Germany, the GermanCTR will continually contribute to the international registries’ network. The quality management concept that is developed together with other primary registries at the ICTRP will be further specified in collaboration with the ICTRP network in 2009 and will be continually implemented into the quality management system of the GermanCTR.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Situation in Germany and the main goals of the German Clinical Trials Register
  5. Implementing the German Clinical Trials Register
  6. Conclusion
  7. Acknowledgement
  8. References

The German Clinical Trials Register has been developed as a tool to enhance transparency in clinical research in Germany. The GermanCTR was successfully implemented as a WHO primary registry and allows clinical trial registration in Germany meeting the ICMJE requirements. Thus, it satisfies the publication policies regarding trial registration of many medical journals (28). Different co-operation partners such as ethics committees and existing local or disease-specific potential partner registries have been identified. The initial collaborations have already been established and will be expanded further.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Situation in Germany and the main goals of the German Clinical Trials Register
  5. Implementing the German Clinical Trials Register
  6. Conclusion
  7. Acknowledgement
  8. References