Academic Strength in Germany

For a long time, Germany fell behind other countries in the area of clinical research. On the one hand, this was because it was only after the reform of the German Medicines Act (Arzneimittelgesetz—AMG) of 1976 (effective as of 1978) that detailed regulations regarding clinical trials were stipulated. On the other hand, infrastructure dedicated to patient-oriented clinical research was lacking at universities and university hospitals and clinical research was conducted only as "after-work research." German universities had no facilities, which were solely dedicated to the professional implementation of clinical trials until the late 1990s. Furthermore, clinical researchers were not as highly esteemed as researchers in fundamental science. It should therefore be no surprise that there were notable shortcomings in the quality of clinical trials in Germany when measured against international standards. Until the late 1990s, globally acknowledged trials, which produced lasting and significant results, remained the exception in Germany. In terms of published trials in internationally acclaimed journals (Lancet, NJM), Germany remained a nonstarter from 1993 to 1997 with only 3% of the 637 published randomized clinical trials coming from this country. In contrast, 38% of these studies came from the United States and 14% from Great Britain.¹

(KKS NETWORK)

The above-mentioned shortcomings not only influenced patient-oriented industrial clinical research but also academic patient-oriented clinical research. Clinical research going beyond industry-sponsored studies is vital from a patient and general healthcare perspective: The emphasis of investigator-initiated trials (IITs) is on the improvement and further development of existing therapies. Academic clinical trials are therefore of crucial importance for healthcare provision, as they answer questions which are of secondary interest, or no interest at all, to the pharmaceutical industry. Such trials, for instance, prove the "true value" of a therapy after it is introduced into everyday clinical practice, including—and especially—in comparison to other, existing therapeutic measures (comparative effectiveness research). This applies to drug mono-therapies as well as to more complex, multi-modular combination therapies and for the areas of non-drug therapy and diagnostics.

Because of the acknowledged importance of clinical research for public health, the situation described above was highly criticized by public bodies—particularly the German Council of Science and Humanities (Wissenschaftsrat) and the German Research Foundation (Deutsche Forschungsgemeinschaft—DFG).² The criticism led to the establishment of a new funding program within the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung). About 12 years ago, so-called Coordinating Centers for Clinical Trials—CTC, Koordinierungszentren für Klinische Studien (KKS)—were established as infrastructural means to strengthen academic clinical research. The aim was to promote patient-oriented clinical research directly at the sites where academic and scientific training, as well as research and healthcare provision, take place pursuant to Anglo-Saxon models. As institutions of universities/medical faculties, the Coordinating Centers for Clinical Trials were meant to establish and develop awareness for internationally competitive clinical research and to facilitate the planning and conduct of such clinical trials for scientists, physicians, and clinicians by providing professional trial support services.

The investment paid off: During the subsequent years, Germany caught up and the quality of academic clinical research has since continuously improved. The infrastructure measures have, for instance, helped research facilities cope with the regulatory changes following the establishment of the 12th Amendment of the German Medicines Act (AMG) in August 2004, which transferred the European Directive 2001/20/EG into German law. Until then, the requirements for conducting non-commercial trials (IITs—investigator-initiated trials) were not fully comparable to those for clinical trials carried out during the course of industrial drug development. The stricter requirements have led to the expectation for a sharp decline in academic clinical research.

Thanks to the dedicated structures, universities and university clinics were able to take on the additional responsibilities as sponsor of a clinical trial pursuant to the amendment and to carry out their role in supervising, monitoring, and auditing the conduct of the clinical trial in accordance with GCP requirements.

Between August 2004 and December 2008, the Federal Institute for Drugs and Medical Devices (BfArM) received a total of 5,000 applications for clinical trial authorizations. The PEI processed about 800 applications during this period. Germany belongs among the leading countries in the European Union with these numbers. The percentage of applications submitted for investigator-initiated trials in comparison to industrial research has been between 16% and 20% (2004 was an exception: 7.5%)—this is comparable to figures prior to the 12th amendment.³ The competent authority specifically attests the high professionalism and quality of the IIT applications compiled with CTCs support.

Founding the CTCs and KKS Network

The realization of IITs requires a high level of medical, scientific, and methodical competence as well as specialized expertise; it was mandatory to release them from their niche position as "sideline activity" of physicians whose main job was to provide medical care to patients. Since 1995 the federal government has continually enhanced its funding in the area of clinical research: The first infrastructural measure specially tailored to this end was the establishment of CTCs at 12 universities since 1998. Approximately 35 million Euros in funding were made available for this purpose. The objective of the CTC is to achieve lasting improvement of patient-oriented clinical research in Germany, to carry out academic (non-commercial) and industrial clinical trials in collaboration with healthcare institutions, and, where appropriate, to develop the necessary procedures for these objectives.⁴ In order to achieve standardized and comprehensive quality assurance, the centers were connected to one another, first as a working group, then as a consortium—the KKS Network (KKSN), Network of the Coordinating Centers for Clinical Trials. Today the KKS Network comprises 16 institutions engaging nearly 500 employees nationwide—and it continues to grow (Figure 1).

Figure 1. The number of employees in the CTC network, KKS Network, has increased more than five times in less than a decade.

On the basis of the CTC funding scheme, the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung—BMBF) started to fund the development of an additional six Clinical Trial Centers (CTC) at German medical faculties/university hospitals with a budget of 24 million Euros in 2007. The prerequisite for this funding was an existing infrastructure for the implementation of clinical trials at the medical faculty/university hospital. The focus of the new funding scheme was slightly different to the initial funding of the CTCs: funding is for the infrastructure of the clinical centers of the university hospitals (resources for the conduct of clinical trials—study nurses—or the promotion of young clinical researchers). The funding shall enable the clinical centers to fully utilize the recruitment potential of the university hospital. All six centers funded by the BMBF through this program now belong to the KKSN.

KKSN: responsibilities and work areas

The KKSN offers a broad range of scientific services. Partners from industry and academia gain access to first rate infrastructure with adjacent hospitals, medical practice networks, and trial personnel (experienced investigators, biometricians, study nurses, project managers, trial monitors, etc.). The members of the KKSN supervise trials investigating almost all indications and collaborate with medical associations, study groups, and other—including European—federations. KKSN is currently supporting trials in 20 countries.

According to KKSN's 2009 statistics, in 43% of cases, CTC-supported trials are sponsored by industrial partners and 48% are covered by non-industrial sponsors—9% other.⁵ In clinical trials where a CTC assumes central responsibilities, the percentage of non-commercial sponsors is even higher, 72% (Figure 2). This demonstrates the strong demand for trial support for IITs. The KKSN offers specialized consulting services for IITs within this remit.

Figure 2. Non-commercial sponsorship holds a slight edge over industrial.

CTCs often support their customers from the first project plan draft all the way through to publication—and are either fully or partially responsible for the individual trial elements. The areas covered usually encompass the study plan; the authorization and approval procedure at ethics committees; the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte—BfArM) or the Federal Agency for Sera and Vaccines (Paul-Ehrlich-Institut—PEI); trial project management; quality assurance; trial monitoring; data management; and evaluation—all the way through to publication.

The supervised IITs often assess very complex therapy procedures, which not only administer drugs but also apply procedures such as surgery, radiation treatment, and treatment with medical products. These trials require as much intensive support as conventional clinical trials to gain marketing authorization (Figure 3).

Figure 3. The hematology/oncology category had the highest apportionment.

IITs can get off to a good start with the help of timely support regarding the procurement of third-party funding (e.g., within the scope of funding programs or from industrial sources) and through advice regarding the proper submission of trial applications. The fact that the experts at the individual CTC manage to create an interface between methodical and clinical domains has a particularly positive effect on IIT realization. Chronically under financed IITs cannot solicit these services from any other source at comparable conditions.

What almost all of these projects have in common is that they are virtually solely "investigator driven" (i.e., initiated and motivated by a medical and scientific need to improve therapy provision). These trials hardly encounter any commercial interest and receive very little financial support. This is true despite the fact that these and further examples from oncology, neurology, psychiatry, surgical specialties, and pediatrics all demonstrate the importance of such trials as the respective illnesses are often life-threatening. Moreover, there is only a limited amount of treatment options in each case. The participating clinicians attest the CTC has a high level of competence. Almost all of the trials mentioned were made possible through the participation of CTC institutions.

Another important fact can be regarded as a direct positive result of the existence of CTCs: the 12th German Medicines Act amendment did not lead to a significant decline in IITs. The new requirements were taught to clinicians by means of topic-focused German Medicines Act amendment modules and integrated into the KKSN standard curriculum for advanced chief investigator training. Today, many hospitals stipulate a CTC pre-consultation as soon as a faculty accepts sponsorship for a clinical trial. CTC is fully integrated into the sponsor's quality assurance process and the scientific and methodological advice supports the investigator to fulfill the increased requirements according to the German Medicines Act.

Institutionalized partnerships The KKSN is an institutionalized partner of medical competence networks. For instance, in 2003 the HIV Network assigned to CTC Cologne (ZKS Köln - previously KKS Köln) with the task of developing and maintaining a database of the hitherto largest HIV patient cohort in Germany. This database is of significant interest for industrial partners as well.

The development of a comprehensive biomaterials bank as core project of the Heart Failure Competence Network (Kompetenznetz Herzinsuffizienz—KNHI) constitutes another prime example. The administration of all information takes place via a central, Internet-based biomaterials database, which was established in the CTC Leipzig (Figure 4).

Figure 4. A working context of a coordination center for clinical trials.

KKSN knowledge products

Several products have been developed with the expertise of KKSN employees, such as:

• Standard operating procedures (SOPs)

• SAS macros for standardized evaluation and report generation

• Pharmacovigilance manual which specifies all aspects of pharmacovigilance obligations during clinical trials

• Innovative software solutions (MedDRA coding tool) for platform, version, and study independent application.

These products are developed according to international standards, provide guidance to meet GCP-requirements, and help to save time and costs.

The question of how costs for IITs can be minimized without having to make concessions in quality assurance constitutes the principle question of the ADAMON Project—which is funded by the BMBF. As the sponsor determines how much monitoring is required, the project aims to ascertain how the costly and labor-intensive monitoring procedure can best be designed so as to achieve an adequate balance between requirements and costs. The project was initiated by the KKSN and is supported by the Federal Institute for Drugs and Medical Devices (BfArM). Twelve multi-center trials in 100 centers encompassing over 3,200 patients will compare "full" monitoring to an adapted, risk-graded monitoring procedure with regard to the effect on the quality of trial implementation.

Figure 5. There was significant growth in just 10 years.

Adequate framework conditions

KKSN campaigns on a national and international level for the promotion of investigator initiated clinical trials. The German Clinical Trials Register, for example, (Deutsches Register Klinischer Studien—DRKS, http://www.germanctr.de) is a WHO-acknowledged trials register, which has been integrated into the so-called primary register within the WHO platform since October 2008. The DRKS was developed by the CTC Freiburg (Studienzentrum Freiburg) and the German Cochrane Center.

Figure 6. The objectives of trials supported by the CTC-Network.

Moreover, the KKSN also assesses and comments on the effect that planned revisions of the regulatory framework will have on IIT implementation and lobbies the legislator for adequate framework conditions. For example, the KKSN is represented within a consultation group for X-ray and radiation protection and within a work group for subject insurance in non-commercial clinical trials. It also participates in hearings regarding law amendments—such as those concerning the AMG. Furthermore, the KKSN has taken on an active role as national partner in the establishment of a European research network called European Clinical Research Infrastructures Network (ECRIN). Cooperations, for example with the Swiss Clinical Trial Organization (SCTO), help to strengthen pan-European interests. In addition, the KKSN is highly involved in an international working group, initiated by the Federal Ministry of Education and Research (BMBF). Within the frame of the Global Science Forum of the Organization for Economic Cooperations and Development (OECD), the group aims to foster IITs at a global level.

Figure 7. Local tasks hold a slight edge over global tasks.

Members of the KKSN promote the implementation of new regulations for non-commercial sponsors by arranging briefing events and further education courses. Standardized basic and advanced education programs in the clinical field and at partner associations convey and continuously enhance the necessary know how. In collaboration with the Vienna School of Clinical Research, the KKSN developed an online course on good clinical practice, which is held in English.

Public and alternative funding

One of the most pressing issues is to reimburse faculties for the significantly increased costs for clinical trials due to the AMG amendment. Public funds are mandatory for this purpose. The Federal Ministry of Education and Research (BMBF) started initiating tenders to this end as of 2005—and the German Research Foundation (DFG) has participated in this scheme. The program, which has a budget of about 20 million Euros per call and will continue until 2012, is an important step in the right direction. However, the current funds of the BMBF and DFG for clinical research are not sufficient enough to achieve evidence-based regular healthcare provision. Compared to the public funding in other countries, the IITs in Germany are notably (and chronically) under financed. The available funds for similar projects in the United States, for example, are often five to 15 times as much as in Germany.⁶

Figure 8. The majority of trials involve medicinal products.

The savings potential for sponsors or the public health sector through results from patient-oriented clinical research should constitute a crucial incentive for the design of new financing models. There is a need to establish financing models for the future which include all the affected stakeholders from the healthcare system, industry, and public finance. A possible solution could be to establish a research fund comprised of an adequate allocation of contributions from care providers, industry, statutory, and private health insurers as well as tax funds. This area could also be improved through regulatory provisions, which imbed real-practice clinical trials in current research practice.

Herbert Maier-Lenz, MD, Associated Member of the Executive Board, KKS Network, former Director of the Clinical Trials Centre Freiburg, Schauinslandstr 85 Germany, 79100 Freiburg, e-mail: Herbert.Maier-Lenz@maier-lenz.net

Editor's Note: Additional figures are available in the online version of the article at appliedclinicaltrialsonline.com.

References

1. M. Rothmund, "An International Comparison of the Position of Clinical Research in Germany," Dtsch. Med. Wochenschr, 122 (44) 1358-1362 (1997).

2. Deutsche Forschungsgemeinschaft, "Klinische Forschung," Denkschrift, Bonn 1999 (Clinical Research, Memorandum).

3. Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Statistik (website), accessed February 2, 2009.

4. C. M. Seiler, I. Bruns, S. Wolff, W. Lehmacher, M.Löffler, and H. Maier-Lenz, "Das Netzwerk der Koordinierungszentren für Klinische Studien," (The Network of Coordination Centers for Clinical Trials) Lehrbuch Evidenz-basierte Medizin in Klinik und Praxis, (Evidence-based Medicine—Manual) Deutscher ärzte-Verlag (2007).

5. Netzwerk der Koordinierungszentren für Klinische Studien (Hrg.): Das KKS-Netzwerk im überblick, 10 Jahre Koordinie-rungszentren für Klinische Studien, 2009 (KKS Network (ed.): The KKS Network at a glance, 10 years of CTCs).

6. Helga Blasius, "Rechtliche und praktische Rahmenbedingungen für nicht-kommerzielle klinische Studien," Deutsche Zeitschrift für Klinische Forschung, 28-35 (2007), (Legal and practical framework conditions for non-commercial clinical trials).