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Purpose: Current trials on adjunctive treatment with antiseizure drugs often do not reveal results which are relevant for clinical practice., Method: Therefore, an interdisciplinary group of German experts discussed a new framework for future antiseizure drug (ASD) trials in adults. This group included members of the executive board of the German Society of Epileptology, of the German institutes for health technology assessment (HTA), of patient organizations and of drug manufacturers. Agreement was reached by consensus decision making after intensive discussion of the findings of a narrative review of the current literature., Results: The group jointly recommends that ASD trials in adults should be based on and include relevant patient groups, e.g. elderly patients and patients with relevant co-morbidities, should adopt a study duration of at least 12 months, should avoid placebo arms, should include active comparators of clinical relevance, may be designed as open label trials with blinded outcome measurements, should focus on patient relevant outcomes that reflect the impact of benefits and harms of treatments on daily living, such as seizure freedom and seizure severity as well as retention rate, functional outcomes and quality of life as compound measures, and should avoid arbitrary and non-sensitive primary endpoints such as dichotomized changes in seizure frequency., Conclusions: This paper focused on improved head-to-head trials on adjunctive treatment with antiseizure drugs. The group welcomes any further work and discussion to enhance future studies which can be applied to the entire spectrum of potentially meaningful study populations and outcomes., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: The bureaucratic and administrative burden for obtaining the obligatory Institutional Review Board (IRB) approval, which confirms the ethical integrity of a scientific project, is high. In order to participate in multicenter studies, most participating centers in Germany require a local second approval. We investigated the variation in the time it took the participating centers of a non-interventional multicenter study to obtain this approval., Methods: Descriptive investigation of the amount of time it takes to gain an IRB approval for a multicenter observational study on the quality of life of sarcoma patients conducted throughout Germany. Stratified analyses were carried out on the basis of potential predictors of this duration and reasons for requests for revisions by the IRB were identified., Results: 44 applications for ethics approval were submitted to 26 IRBs. To obtain the 25 second approvals took 53.6 days on average (standard deviation 49.8 days, median 34 days). While State Medical Chambers needed an average of 20.3 days for a local second approval, university hospitals needed 72.4 days. 81.3 % of the university IRBs and 33.3% of the IRB of the State Medical Chambers made specific requests. Ten IRBs followed the recommendations of the primary approval without undertaking their own assessment (average 41.3 days), five IRBs examined the application in an abbreviated procedure (51.4 days), and ten examined it thoroughly (67.1 days)., Conclusion: Submitting ethics approval applications for observational studies in a clinical setting involved considerable effort and long waiting times in 2017 and 2018. Simplified review procedures or a waiver of examination by local IRBs do not necessarily mean shorter processing times. In general, there is a continued need for further progress., (Copyright © 2019. Published by Elsevier GmbH.)

Background and Objective: The development and evaluation of interventions in long-term care is time-consuming and expensive due to their complexity. To ensure reproducibility and successful implementation, these interventions must be described and published in a comprehensible and qualitative manner. The aim of this study is to analyze intervention studies from the inpatient long-term care setting with regard to their completeness, reporting quality, transparency and thus reproducibility., Method: The completeness and the reporting quality of the interventions described in the publications were examined in the context of a selective literature review by means of intervention studies from the long-term care setting (n=22). To this end, the Template for Intervention Description and Replication (TIDieR) checklist and the Criteria for Reporting the Development and Evaluation of Complex Interventions in Healthcare 2 (CReDECI2-DE) list were used. Transparency criteria included study registration and access to study protocols., Results: The TIDieR checklist examination revealed that only three studies contained all the information necessary; the CReDECI2 test provided a complete description for only one study. Frequent shortcomings were observed concerning the information on modifications and titrations for the study participants and the location. Protocols were available for eight studies, 14 studies were registered., Conclusions: In terms of science, this means that the reproducibility of scientific findings is limited, which is why they cannot provide secure knowledge. As a result, the practical benefit to be derived from published studies that are accessible to decision-makers is limited as well. As far as publishers are concerned they should pay more attention to the completeness, registration and availability of materials., (Copyright © 2018. Published by Elsevier GmbH.)

Vaccines are among the most effective preventive measures in modern medicine and have led to a dramatic decline and-for a few diseases-even to the elimination of severely infectious diseases. There are some particularities of the risk-benefit assessment of vaccines compared with that of therapeutic drugs. These include the fact that vaccines are applied to healthy individuals with the aim of preventing an infectious disease, while therapeutic drugs are administered to sick people to cure them of an already acquired disease. The acceptable level of risk associated with the application of a vaccine is therefore much lower. In addition, high vaccination coverage can lead to population-level effects (e.g., the indirect protection of unvaccinated individuals) that can confer additional benefits to the population overall. When a marketing authorization application (MAA) for a novel vaccine is evaluated, conclusions are made regarding its quality, safety, and efficacy, and a benefit-risk assessment is carried out accordingly. In contrast, when deciding on the introduction of a new vaccine into a national immunization program or on a recommendation for a specific risk-group, the focus is shifted to considerations of how a licensed vaccine can be best used in a population (e.g., which immunization strategy is most effective in preventing deaths or hospitalizations, or in reducing treatment costs for the health care system). Stringent assessment criteria have been developed that require a robust safety analysis before a new vaccine is administered to humans for the first time in pre-licensure studies. Similarly, criteria are applied for calculating the benefit-risk ratio at the time of the licensure of a new vaccine in addition to during the entire post-licensure period. However, when deciding if and how a licensed vaccine can best be integrated into an existing immunization program, additional criteria are applied that are different, yet complementary to those applied for granting a marketing authorization. These decisions require-in addition to considerations of vaccine quality, vaccine efficacy and safety-conclusions regarding population-level effects combined with an integrative analysis of the local context (e.g., local epidemiology, cost-effectiveness, and acceptance by the population). To serve these objectives, national authorities such as the Standing Committee on Vaccination in Germany (STIKO) have been established to integrate globally developed vaccines into the national context of immunization strategies.

In 2005, the Working Group for the Survey and Utilisation of Secondary Data (AGENS) of the German Society for Social Medicine and Prevention (DGSMP) and the German Society for Epidemiology (DGEpi) first published "Good Practice in Secondary Data Analysis (GPS)" formulating a standard for conducting secondary data analyses. GPS is intended as a guide for planning and conducting analyses and can provide a basis for contracts between data owners. The domain of these guidelines does not only include data routinely gathered by statutory health insurance funds and further statutory social insurance funds, but all forms of secondary data. The 11 guidelines range from ethical principles and study planning through quality assurance measures and data preparation to data privacy, contractual conditions and responsible communication of analytical results. They are complemented by explanations and practical assistance in the form of recommendations. GPS targets all persons directing their attention to secondary data, their analysis and interpretation from a scientific point of view and by employing scientific methods. This includes data owners. Furthermore, GPS is suitable to assess scientific publications regarding their quality by authors, referees and readers. In 2008, the first version of GPS was evaluated and revised by members of AGENS and the Epidemiological Methods Working Group of DGEpi, DGSMP and GMDS including other epidemiological experts and had then been accredited as implementation regulations of Good Epidemiological Practice (GEP). Since 2012, this third version of GPS is on hand and available for downloading from the DGEpi website at no charge. Especially linguistic specifications have been integrated into the current revision; its internal consistency was increased. With regards to contents, further recommendations concerning the guideline on data privacy have been added. On the basis of future developments in science and data privacy, further revisions will follow., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: The objective of this project was to evaluate the quality and quantity of initial applications for a clinical trial according to § 7 of the German Good Clinical Practice (GCP) ordinance (German: GCP-Verordnung, GCP-V), the quality of evaluations of those applications by Ethics Committees (ECs)/Investigational Review Boards (IRBs) in Germany as well as the pattern of EC objections in their reasoned opinions (vote). In order to identify a change over time, the results of the present survey were also compared with a survey performed in 2008., Methods: Based on reasoned opinions issued by the respective EC in charge of the coordinating principle investigator (coordinating EC) in 2011, a written survey among members of the German Association of Research-Based Pharmaceutical Companies (vfa) was conducted in 2012. The answers to the questionnaire were analyzed descriptively. Since the data set collected in 2011 was structurally identical with the data set gained in 2007 both surveys were compared., Results: Of the 24 companies represented on the vfa Clinical Research/Quality Assurance Subcommittee, 75% (18) took part in the survey. Survey evaluation was based on a total of 251 applications of these 18 companies submitted to 43 ECs. These account for about 21% of 1,214 applications for authorization of commercial and non-commercial phase I-IV clinical trials submitted to the regulatory authorities (BfArM and PEI) in 2011. In comparison to 2007, a lower amount of applications (n=251 in 2011 vs. n=288 in 2007) was submitted to a slightly higher number of ECs (43 in 2011 vs. 40 in 2007). The amount of objections increased by 21% from 1,299 (2007) to 1,574 (2011) resulting in an average of 4.5 (2007) vs. 6.3 (2011) objections per application. Overall, the analysis of both formal and content related objections revealed almost the same pattern as in the previous survey. In total, the most frequent objections applied to the patient information and consent form followed in descending order by trial protocol content, miscellaneous, other application documents pursuant to § 7 (2) and (3) GCP-V, formal deficiencies pursuant to § 8 (1) GCP-V, and investigator and site qualifications. A trend towards a slightly increased rate of objections concerning patient information and consent form (+4%) and a minimal decrease in objections concerning investigator and site qualifications (-2%) was observed. As in 2007, about 1 in 6 applications was still incomplete with formal objections. Whilst the proportion of study applications with objections related to the patient information and consent form (+7.2%), the trial protocol content (+11.6%), and documents according to § 7 (2) and (3) GCP-V (+11.8%) increased in 2011 compared to 2007, the amount of study applications with objections related to the investigator and site qualifications decreased by 6.3%., Conclusions: The majority of findings with respect to quantity, quality and main focus of objections reported in the first survey in 2008 were also found in 2012, indicating a shared understanding of applicable measures and criteria by sponsors and ECs on how to ensure patient rights and well-being, data integrity, and high quality documentation in clinical trials.

Patient registries are an important instrument in medical research. Their implementation uses complex software systems to meet the wide spectrum of challenges. There is a wide range of systems available and a critical appraisal of their architecture is needed. Therefore, we developed, based on a systematic review of the literature, a checklist for patient registry software systems (CIPROS) which is organised in 67 items and 10 sections. CIPROS supports developers to assess requirements of an existing system. It also supports the reporting of patient registry software system descriptions in papers and it can be a first step to create standards for patient registry software systems.

Process management (PM) is a valuable method for the systematic analysis and structural optimisation of the quality and safety of clinical treatment. PM requires a high motivation and willingness to implement changes of both employees and management. Definition of quality indicators is required to systematically measure the quality of the specified processes. One way to represent comparable quality results is the use of quality indicators of the external quality assurance in accordance with Sect. 137 SGB V—a method which the Federal Joint Committee (GBA) and the institutions commissioned by the GBA have employed and consistently enhanced for more than ten years. Information on the quality of inpatient treatment is available for 30 defined subjects throughout Germany. The combination of specified processes with quality indicators is beneficial for the information of employees. A process-based indicator dashboard provides essential information about the treatment process. These can be used for process analysis. In a continuous consideration of these indicator results values can be determined and errors will be remedied quickly. If due consideration is given to these indicators, they can be used for benchmarking to identify potential process improvements., (Copyright © 2014. Published by Elsevier GmbH.)

Background: The recommendations in clinical guidelines are based on clinical trial findings and expert opinion. The influence of drug companies on these two factors is illustrated with two examples., Methods: A judicially ordered expert review revealed that the market authorization holder (MAH) of gabapentin manipulated study data. Gabapentin was, therefore, chosen as an example for this article to analyze whether manipulated data serve as a basis for recommendations in German clinical guidelines. A search was carried out for manipulated publications on gabapentin that found their way into guidelines published by the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). To analyze the possible effects of financial ties between guideline authors and drug companies, the S3 guideline on the treatment of psoriasis vulgaris with efalizumab was compared with guidelines whose authors had no conflicts of interest. One of the authors of this article had noted variable prescribing practices for psoriasis among dermatologists while carrying out an economic assessment for a German state Association of Statutory Health Insurance Physicians., Results: The data that had been manipulated by the MAH of gabapentin served as a basis for recommendations to prescribe gabapentin in guidelines that were published by the AWMF. Efalizumab was judged more favorably in the S3 guideline than in a guideline issued by the National Institute of Health and Care Excellence: for example, the evidence for it was judged as good, the use of efalizumab for induction and combination therapy in psoriasis vulgaris was recommended, and efalizumab was said to improve patients' health-related quality of life., Conclusion: Public access to all trial data must be ensured so that independent evaluations are possible. We take the view that the responsibility for creating guidelines should be borne by authors and organizations that do not have any conflicts of interest.

Background: In recent years, personalized medicine (PM) has become a highly regarded line of development in medicine. Yet, it is still a relatively new field. As a consequence, the discussion of its future developments, in particular of its ethical implications, in most cases can only be anticipative. Such anticipative discussions, however, pose several challenges. Nevertheless, they play a crucial role for shaping PM's further developments. Therefore, it is vital to understand how the ethical discourse on PM is conducted, i.e. on what - empirical and normative - assumptions ethical arguments are based regarding PM's current and future developments., Methods: To gather this information, we conducted a qualitative interview study with stakeholders in the German health care system. Our purposive sample included 17 representatives of basic research, clinical research, health economics, regulatory authorities, reimbursement institutions, pharmaceutical industry, patient organizations, as well as clinicians and legal experts involved in PM developments or policy making. We used an interview guide with open-ended questions and analyzed transcriptions of the interviews by means of qualitative content analysis., Results: The respondents addressed a multitude of concerns in the context of research on as well as application of personalized preventive and therapeutic measures both on the individual and on the societal level. Interestingly, regarding future developments of PM the ethical evaluation seemed to follow the rule: the less likely its application, the more problematic a PM measure is assessed. The more likely its application, on the other hand, the less problematic it is evaluated., Conclusions: The results of our study suggest re-focusing the ethical discourse on PM in Germany towards a constructive ethical monitoring which ensures to include only, nevertheless all of the actual and/or potential concerns that are ethically relevant in order to allow balancing them against the actual and potential ethically relevant benefits of PM measures. To render this possible, we propose a strategy for evaluating ethical concerns in the context of PM.

In recent years studies not falling under the German Pharmaceutical Law ("non-drug trials") have also been increasingly expected to be conducted according to Good Clinical Practice (GCP) in order to ensure that uniform standards are maintained for data quality and patient safety. However, simple transfer of the GCP criteria is not always possible and often not useful. Given the fact that research questions regarding non-drug interventions are common in primary care (e.g., general practice), the "Network for Clinical Studies in General Practice" has developed a manual for planning and conducting non-drug trials. This manual is based on the GCP guideline, taking account of the conditions and circumstances in primary care settings. Both structure and relevant content of the manual are presented in the article. (As supplied by the authors)., (Copyright © 2012. Published by Elsevier GmbH.)

The results of clinical, preferably randomized controlled trials (RCTs) form the backbone of drug approval decisions and benefit assessments of medical interventions. Whereas drug approval studies often answer at least some of the relevant questions posed in a benefit assessment, the situation is totally different for non-drug treatments and diagnostic tests, as the requirements for market entry are not as high in these fields. Overall it must be concluded that in the past and up to the present time there have been insufficient (financial) incentives for manufacturers or providers of medical interventions to conduct clinical trials concerning patient-relevant benefits both in the field of drugs and particularly in non-drug interventions. This has led to a lack of studies that, in an appropriate comparison with sufficient certainty of results, provide data on the patient-relevant benefits or added benefits of a medical intervention. In this context, it is secondary whether these are 'independent' studies, the more so as 'dependencies' can never be excluded and can become especially problematic in cases where they are not easily recognized by declaration of sponsorship. The Institute of Quality and Efficiency in Health Care (IQWiG) is willing to promote the creation of appropriate funding opportunities for important study projects of clinical research groups fulfilling the criteria for a high-quality patient-oriented clinical trial on a relevant research question, and is currently doing so together with interested parties., (Copyright © 2013 S. Karger AG, Basel.)

Background: In Germany, clinical trials and comparative effectiveness studies in primary care are still very rare, while their usefulness has been recognised in many other countries. A network of researchers from German academic general practice has explored the reasons for this discrepancy., Methods: Based on a comprehensive literature review and expert group discussions, problem analyses as well as structural and procedural prerequisites for a better implementation of clinical trials in German primary care are presented., Results: In Germany, basic biomedical science and technology is more reputed than clinical or health services research. Clinical trials are funded by industry or a single national programme, which is highly competitive, specialist-dominated, exclusive of pilot studies, and usually favours innovation rather than comparative effectiveness studies. Academic general practice is still not fully implemented, and existing departments are small. Most general practitioners (GPs) work in a market-based, competitive setting of small private practices, with a high case load. They have no protected time or funding for research, and mostly no research training or experience. Good Clinical Practice (GCP) training is compulsory for participation in clinical trials. The group defined three work packages to be addressed regarding clinical trials in German general practice: (1) problem analysis, and definition of (2) structural prerequisites and (3) procedural prerequisites. Structural prerequisites comprise specific support facilities for general practice-based research networks that could provide practices with a point of contact. Procedural prerequisites consist, for example, of a summary of specific relevant key measures, for example on a web platform. The platform should contain standard operating procedures (SOPs), templates, checklists and other supporting materials for researchers., Conclusion: All in all, our problem analyses revealed that a substantial number of barriers contribute to the low implementation of clinical research in German general practice. Some issues are deeply rooted in Germany's market-based healthcare and academic systems and traditions. However, new developments may facilitate change: recent developments in the German research landscape are encouraging.

Childhood obesity is recognized by the World Health Organization as one of the most serious public health challenges of the 21st century. Current treatment recommendations consider the role of pharmacotherapy in the treatment of childhood obesity, as an adjunct to lifestyle modifications. This article focuses on key requirements for paediatric development of medicines for obesity in Europe with reference to the European Medicines Agency guideline and a review of Paediatric Investigation Plans (PIP) submitted for this condition, under Regulation (EC) No. 1901/2006 on medicines for paediatric use. To date the European Medicines Agency (EMA) received four paediatric investigation plans for childhood obesity. Issues encountered during the assessment of paediatric investigation plans were all related to the characteristics of the patient population, trial design, choice of endpoints, and safety aspects. Although the number of paediatric investigation plans submitted to the European Medicines Agency thus far is limited, current experience highlights the need for clinical trial protocols that are in line with the specific European guideline. Divergent approaches should be discussed with regulatory authorities before paediatric trials are initiated and included in paediatric investigation plans.

Non-interventional studies (NIS) have for decades been an established part of post-authorisation medicinal research. As early as the mid-nineties, there were at least rudimentary demands for controllable data quality. Beginning with the recommendations of the Federal Institute for Drugs and Medical Devices (BfArM) on the execution of non interventional (observational) studies of 1998 and finally with the guidelines and recommendations for ensuring Good Epidemiological Practice (GEP), with the VFA (Verband der forschenden Arzneimittelhersteller [German Association of Research-Based Pharmaceutical Companies]) - Recommendations for the Improvement of Quality and Transparency of NIS and the joint recommendations of BfArM and PEI (Paul-Ehrlich-Institut) on the execution of NIS, pharmaceutical companies are required to monitor and/or verify quality in the course of a project. According to a survey of pharmaceutical companies 2010, about one third of the companies surveyed to date carry out such quality controls on site, at participating study centres. This report deals with the results of such quality control measures in 4 completed projects. The control rates defined in the respective cohort study plans, the measures carried out on site and any consequent measures, such as adjustment of forms, reduction of consultation time and necessary organisational changes are described. A high level of agreement between the data collected and the original patient documents is found, comparable to that in clinical trials.

So far there has been no consensus on the criteria which confirm the validity of scientific contributions in conventional medicine (CM) and complementary/ alternative medicine (CAM). An interdisciplinary group of experts from various disciplines within each of the areas of medicine held six well-documented sessions in an effort to reach a consensus. The group agreed that the methods to confirm the validity of clinical trials are identical in CM and CAM. There are differences in research strategies and there may also be differences in interpreting the results, depending on the concept of medicine., (Georg Thieme Verlag KG Stuttgart, New York.)

A number of publications on publication bias or selected outcomes reporting have led critics to doubt that the pharmaceutical industry is able to remain objective in its research activities. This paper discusses the prerequisites for objective research and to what extent these are met by research projects conducted by the pharmaceutical industry. Problems with meeting objectivity criteria on the part of the pharmaceutical industry will be highlighted, distinguishing between industrial research activities themselves (i.e., studies) and the publication of data resulting from such research. The aim of the discussion is to illustrate how and which research-guiding conditions can ensure that sponsors indeed meet the criteria for objective research.

In order to provide a central portal for information on clinical research in Germany and thus to facilitate the search of planned, ongoing and completed clinical trials, the German Clinical Trials Register (GermanCTR) was implemented in cooperation with the WHO's registries network. It is an open access online register of clinical trials conducted in Germany, which allows all users to search for, register and share information on clinical trials. The project is funded by the Federal Ministry of Education and Research and is implemented at the Institute for Medical Biometry and Medical Informatics of the University Medical Center Freiburg as a joint project of the Clinical Trials Center Freiburg and the German Cochrane Center. Since October 2008 the GermanCTR is an approved WHO Primary Registry and allows clinical trial registration in Germany according to the requirements of the International Committee of Medical Journal Editors (ICMJE). Reasons for a national trials register, general and technical aspects of implementing the GermanCTR as well as the national and international integration are described here.

Clinical trials in children are mandatory to generate data on new drugs as well as on drugs used off-label or for unlicensed indications. The EU Paediatric Regulation introduced in 2007 provides the background, goals, and requirements for pediatric clinical trials. The German Paediatric Network (PAED-Net) was established in 2002 with a public grant from the German Ministry of Education and Research with the aim of developing competence, infrastructure, networking, and education for pediatric clinical trials. The network, consisting of six pediatric clinical units and a coordinating office, has progressed very well and has achieved valuable improvements concerning the conduct of pediatric clinical trials. In addition, training programs have encouraged knowledge about clinical trials in investigators and nurses and have made medical professionals as well as the public aware of the need and advantages of trials in children. Although these trials are still challenging from the ethical, scientific, and clinical points of view, quality-controlled data are the prerequisite for sharing therapeutic innovations for children and for applying the principles of evidence-based medicine to the youngest patient population.

Background: Only data of published study results are available to the scientific community for further use such as informing future research and synthesis of available evidence. If study results are reported selectively, reporting bias and distortion of summarised estimates of effect or harm of treatments can occur. The publication and citation of results of clinical research conducted in Germany was studied., Methods: The protocols of clinical research projects submitted to the research ethics committee of the University of Freiburg (Germany) in 2000 were analysed. Published full articles in several databases were searched and investigators contacted. Data on study and publication characteristics were extracted from protocols and corresponding publications., Results: 299 study protocols were included. The most frequent study design was randomised controlled trial (141; 47%), followed by uncontrolled studies (61; 20%), laboratory studies (30; 10%) and non-randomised studies (29; 10%). 182 (61%) were multicentre studies including 97 (53%) international collaborations. 152 of 299 (51%) had commercial (co-)funding and 46 (15%) non-commercial funding. 109 of the 225 completed protocols corresponded to at least one full publication (total 210 articles); the publication rate was 48%. 168 of 210 identified publications (80%) were cited in articles indexed in the ISI Web of Science. The median was 11 citations per publication (range 0-1151)., Conclusions: Results of German clinical research projects conducted are largely underreported. Barriers to successful publication need to be identified and appropriate measures taken. Close monitoring of projects until publication and adequate support provided to investigators may help remedy the prevailing underreporting of research.

Data Monitoring Committees (DMC) are increasingly becoming integrated into the methodical procedure of clinical trials, in order to support sponsors in their central role. Whereas monitors and auditors, respectively, give quality assuring recommendations in compliance with GCP, an implemented DMC is able to give sponsors far-reaching recommendations owing to its access to unblinded data. Besides the main intention of enhancing safety during the conduction of clinical trials, the premature termination of clinical trials due to insufficient efficacy of the investigational medicinal product may be a result. Based on the European Guideline EMEA/CHMP/EWP/5872/03 Corr and based on published literature, criteria and crucial aspects for implementing this independent committee are being named If, in the course of a clinical trial, the implemented DMC notices an alteration in the risk-benefit assessment in the context of pharmacovigilance, immediate notification obligations of the Sponsor to the higher federal authorities and to the ethics committees arise.

After publication of the "Good Practice Secondary Data Analysis" (GPS) in 2005, the scientific use of secondary data has further increased. Based on several feedbacks to the first version of this guideline, the Working Group "Collection and Use of Secondary Data" (AGENS) of the German Society of Social Medicine and Prevention (DGSMP) together with the working group 'Epidemiological Methods' of the German Society of Epidemiology (DGEpi), the German Society for Medical Informatics, Biometrics and Epidemiology (GMDS) and the German Society of Social Medicine and Prevention (DGSMP) undertook the first revision of the GPS, which will be implemented in the beginning of 2008. The second version of the GPS was restructured in relation to the first version. Now, the numbering of the guidelines is the same as that of the Good Epidemiological Practice (GEP). The GPS guidelines also have the same wording as in the GEP. The specific conditions and requirements of secondary data analysis were addressed in the explanations of the guidelines and their recommendations. The glossary at the end of the GPS was extended. In the last three years the GPS has become established as a standard for secondary data analyses. Additionally, the GPS may be used as a basis for contractual arrangements between data owners and researchers. This version of the GPS is valid to the end of 2010.

Pharmacokinetic investigations of a drug - and of its pharmacologically active metabolite, if necessary - represent an essential part of clinical trials. The European Union (EMEA, European Medicines Agency) strictly regulates the separation and quantification of a drug from biological matrix, e.g. blood, urine, tissue, and others. These GCP (Good Clinical Practice) and GLP (Good Laboratory Practice) guidelines have to be considered and documented for the planning of the investigation, the administration of the test drug, the sampling, and the transport of samples. The following sample preparation, analytical measurements, and biometric calculations have to be performed only by validated procedures. Similar requirements are necessary for the final pharmacokinetic modelling, the statistical presentation of data, and the final report. In this article the most important aspects concerning the performance of a pharmacokinetic investigation will be presented., (Copyright 2008 S. Karger AG, Basel.)

Reliable and correct data capture and safe data management are an inevitable prerequisite to gain valid data in clinical studies. The biostatistical analysis is the basis from which medical consequences about efficacy and safety of the treatment can be driven. The functional role of data capture and data management in relation to the study protocol, development of report forms, data flux between the involved institutions, and the data capture systems will be investigated. Main points of the data capture are the rationale of the study, the protocol, and the statistical analysis plan. Modularity, uniqueness, and reduction on the needs of the study protocol designate a good documentation form. Practical considerations will be given. Prompt and efficient communication between all involved participants is the organizational prerequisite for valid data, independent from the data capture system. Online data capture will displace the classical paper documentation form, however, accurate and careful documentation will remain. Data capture and data management are a crucial and cost-intensive chapter of a clinical study, formed by the technical ability and the team play of clinical principal investigators, biostatisticians, computer scientists, monitors, and the organizers of the study., (Copyright 2008 S. Karger AG, Basel.)

Objectives: With Standard Operating Procedures (SOPs) the conduction of clinical trials should be standardized so that the results are comparable and traceable. This aim can only be reached if the staff of clinical trials really uses the SOPs. Therefore, we conducted a survey to explore the use and usability of SOPs in clinical trials and to identify problems for their handling., Method: Standardized, validated questionnaire among the staff of all 12 coordination centers for clinical trials in Germany (n = 238), anonymous, descriptive analyses, Results: A return rate of 58.8% was reached. When having questions about the daily work 18.4% more likely ask a colleague than read the corresponding SOP (13.8%). For the relevance of SOPs 16.9% of the staff regard less than 10% of SOPs as relevant for them. Exclusively working with electronic SOPs are 4%., Conclusions: The results of the survey indicate that improvements for the handling of SOPs are necessary. They could be used to design a computer-based information retrieval system for SOPs to increase the ease-of-use and usefulness of SOPs in clinical trials.

The procurement, transport, storage, manufacturing or compounding, the application, disposal, documentation, and the quality assurance of investigational medicinal products (IMPs) have to be done according to the pharmaceutical sciences. Medicines related to clinical trials in the European Union are regulated in volume 10 of the EudraLex. The rules for commercially manufactured medicines for human use are not valid for medicines which are individually compounded for a certain patient in the pharmacy. They are also not valid for medicines dedicated for experiments in research and development. The present article describes standards concerning the participation of the pharmacy in clinical trials, the pathway of the drug including the role of the study personnel, and its qualification and training. The issue of stability and compatibility of IMPs is an important topic which may influence the outcome of clinical trials. To avoid quality shifts Standard Operating Procedures (SOPs) have to be established., (Copyright 2008 S. Karger AG, Basel.)

In this contribution we discuss some fundamental aspects of biostatistics in the context of research in clinical oncology. Starting with a general presentation of basic principles of confirmatory statistics we deal with specific questions which typically arise in practical situations. This covers the importance of prespecification of statistical analyses before looking at the data as well as the judgment of multiple p-values and the interpretation of subgroup analyses. Subsequently we propose essential principles and techniques for the design and analysis of controlled clinical trials, which are relevant to achieve valid results with regard to cause-effect relationships from clinical observations. We specifically point out that an exact definition of the whole research design together with the methods of analysis and evaluation as well as planning of interim analyses and possible termination strategies have to be defined clearly in advance. General hints with regard to reporting standards conclude this chapter. In the final chapter we discuss general ideas behind meta-studies and demonstrate by means of a small example some basic analytical techniques for the summarization of single study results., (Copyright 2008 S. Karger AG, Basel.)

The preclinical development of novel anticancer compounds mainly resembles the same principle as valid for other drug classes. New target structures on tumors are identified within academic or industrial fundamental research groups enabling a selective attack of cancerostatics. After the proof of principle in molecular or cellular systems, substance candidates are selected which undergo a stepwise preclinical testing. This procedure consists of cell culture models (in vitro) and animal experiments (in vivo) using suitable tumor models. With selected lead compounds the pharmaceutical formulation is prepared, and the legally required preclinical toxicological investigations are performed before initiation of clinical phase I studies. There is one special feature distinguishing cytostatics from all other drugs - their narrow therapeutic index. This constraint is to be considered already in early phases of anticancer drug development, and a special focus should be given to the revealing of potential side effects. This contribution especially gives attention to this aspect of preclinical anticancer drug development. Further on, focus is put on target-oriented compounds, whose preclinical development generates special challenges., (Copyright 2008 S. Karger AG, Basel.)

Nowadays results of clinical studies in oncology are often first found and commented in the news media because of their high relevance to the pharmaceutical market. The limits and pitfalls of clinical studies are manifold and not always appreciated even by specialists as well as journalists and politicians. The planning of a study is a most crucial phase, and most deficits are due to inappropriate design and conduct of a study. Adequate and skilful interpretation of a study is often hampered by many known but mostly overlooked variable pitfalls. Today there is an overrepresentation of pharmaceutically sponsored studies and a painful lack of well-designed academic studies with really meaningful endpoints for patient care. This paper touches several important aspects of today's shortcomings of clinical studies in oncology and highlights the importance of strengthening the academic clinical research. Evidence-based medicine needs to be more clinically relevant, and therefore we need well-designed, and critically interpreted studies in the future., (Copyright 2008 S. Karger AG, Basel.)

Biologics are a heterogeneous group of substances with unique characteristics that are clearly distinguishable from classical cytotoxic drugs. Current concepts for clinical oncology drug development are mostly based on experiences obtained with cytotoxic agents and therefore do not (or not properly) account for several aspects that are crucial when it comes to the use of new biologics. This can lead to extreme cases where new substances that clearly bear a potential of antitumor efficacy do not reach needed levels of significance in clinical trials or are never introduced to advanced stages of clinical testing at all. In order to increase the number of biologics that can be successfully led through all phases of clinical development the currently established standards will have to be reconsidered and modified in such a way that they meet the specific needs of the tested biologics. It is important to mention that such an agent-specific adjustment of clinical development paradigms does not mean that the currently demanded high standards of safety and quality will have to be lowered by any means. The most striking arguments for a new clinical development paradigm are exemplified for therapeutic tumor vaccines but also hold true for related biologics., (Copyright 2008 S. Karger AG, Basel.)

This contribution deals with all important organizational and administrative aspects of clinical studies in German speaking countries. All trials are to be executed in accordance with the Good Clinical Practice (GCP) Guidelines. GCP applies to the process of designing, conducting, recording, and reporting of clinical studies. Compliance with GCP facilitates the mutual acceptance of resulting clinical data by the respective regulatory authorities worldwide. Before initiating a clinical study the investigator has to obtain written and dated approval from the responsible ethics committee, the competent authorities, and the hospital administration. The investigator's study file contains all essential study documents. One of the most important tasks of an investigator is to properly inform the prospective subjects and to obtain their informed consent. All relevant treatment-related information has to be recorded in the patient files. These source data are transferred to case report forms. During monitoring visits, audits, and inspections, source data verification will be performed routinely. Any adverse events (AEs) must be documented according to the CTCAE, the Common Terminology Criteria for Adverse Events. All serious adverse events (SAEs) have to be reported to the sponsor immediately. At the end of the study a termination visit is performed, and all authorities are officially informed about the termination of the trial., (Copyright 2008 S. Karger AG, Basel.)

Background and Objective: According to the Medical Association's professional code of conduct a consultation of the responsible ethics committee has to be undertaken prior to biomedical research. Up to date there has been no systematic analysis of published results after an approval from the research ethics committee of the Medical Association Westfalen-Lippe. A measure for the importance are publications of concluded trials. This work presents a comprehensive collection and evaluation of clinical trials that were approved in 1996., Methods: Clinical trials that were approved by the ethics committee in the year 1996 were analysed concerning their publication parameters, if results have been reported to the ethics committee, the design of the study and their funding. Publications were found by database mining in the Internet sources "Pubmed" and "ISI Web of Knowledge"., Results: 70 % out of the 99 approved clinical trials were published as specified in the initial proposal, whereas in 2 % only aspects of the proposal were published. In 21 % of the cases only publications in closely related subjects could be identified. 7 % however remained unpublished. Of these studies 63 % were designed as mono centre study and 37 % as multi centre studies. The time from approval of the study until publication was 46 months (median value). Furthermore the analysis revealed, that 45 % of the studies were funded by industry., Conclusion: This work represents an unprecedented and detailed analysis of the clinical studies approved by a German ethics committee. In the course of this work a comprehensive catalogue with criteria to facilitate a collection and tracking mechanism was established. This should enable the ethics committee to comply with their new duties. A great amount of the clinical trials were presented in publications to the scientific community.

Evidence-based medicine is the explicit use of the currently best available scientific data for decision-making in the management of individual patients, with guidelines being among the instruments for its implementation. Publication of the German S3 guideline on the treatment of plaque-type psoriasis is a mile-stone for German dermatology, as it is the first dermatologic guideline at this highest level of evidence. Standardized analyses of the respective publications provide the basis for this guideline. This article explains the principles of such an analysis, so the reader can gain insight into the methodology of a crucial aspect of guideline generation. This information is of general relevance, as it provides help for every physician who wishes to critically read original scientific publications.

The performance of the German pharmaceutical industry, future challenges and obstacles to quality improvement are assessed from a systems-of-innovation perspective, using appropriate innovation indicators. The current close-to-market performance indicators paint an unfavourable picture. Early R&D indicators (e.g., publications, patents), however, reveal a positive trend. A lot of obstacles to quality improvements are identified with respect to knowledge base, knowledge/technology transfer, industrial R&D processes, capital markets, market attractiveness and both regulatory and political framework conditions. On this basis, recommendations will finally be derived to improve quality in the pharmaceutical industry.

A German working group had requested to introduce a national clinical trials registry. Keeping in mind the numerous existing German clinical trials registries requirements of such a registry, as well as the current international harmonization initiatives and the possibility of creating such a national registry were considered. To avoid multiple recording especially in regard to multicentric, international trials, it is recommended -- based on the spirit of the WHO recommendations -- to use the trial registry of the National Institutes of Health. For the time being, this trial registry represents the by far most frequently used database available for public use. It is equipped by internationally active pharmaceutical companies as well as universities and research facilities from all over the world and actually contains approximately 23,500 clinical studies. A national clinical trials registry could be installed at best only complementary and would have to get its data directly from the international registry without additional burden by research facilities.

Background: Evidence-based medicine requires careful appraisal of published data derived from experimental and clinical studies. Based on classification of biomedical research reports, evidence levels can be determined and recommendations for therapeutic decisions can be made., Methods: A classification system for clinical studies was developed. It was evaluated in classifying the reports published in Der Ophthalmologe during 2003-2004 (study design: descriptive cross-sectional study, case series)., Results: In the 2-year interval, 70 longitudinal and 95 cross-sectional studies were published. The vast majority of the longitudinal studies were interventional cohort studies. Not considering case reports, 73% of the original articles were longitudinal prospective studies, 1% were retrospective (case-control) studies, and 26% were cross-sectional studies., Conclusions: The study design of all published articles could be classified using the classification system. This classification system proves to be applicable in the context of clinical studies in ophthalmology and may be helpful in the process of critical appraisal of the literature and synthesis of clinical evidence and an evidence-based recommendation.