Extension of Indication for Authorised Oncology Products in the European Union: A Joint Effort of Multiple Stakeholders

After marketing authorisation, the development of a medicinal product often continues with studies investigating new therapeutic indications. Positive results can potentially lead to changes to the terms of the marketing authorisation, such as an extension of therapeutic indication(s). These studies can be initiated and sponsored by the marketing authorisation holder (MAH) or by others. When results from an investigator-initiated trial suggest that an authorised medicinal product is safe and effective for a new therapeutic indication, physicians may want to treat their patients with this medicinal product. In such a situation, it is desirable to extend the therapeutic indication(s) via the regulatory approval process, as this can facilitate patient access within the European Union. There may however be challenges when the MAH did not conduct the study and might not have access to the data. In this perspective, we focus on the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product based on results from investigator-initiated trials. We address: (1) the advantages of an extension of indication; (2) the regulatory requirements for a variation application; (3) investigator-initiated trials as a basis for regulatory approval; (4) the role of the MAH in extending the indication. With this article, we want to emphasize the importance of a collaborative approach and dialogue between stakeholders with the aim to facilitate access to effective medicinal products.

Portuguese Authorship in Published Clinical Trials: Differences in Industry and Investigator Initiated Trials

Introduction: The aim of this study was to investigate the Portuguese authorship in publications resulting from trials initiated by the industry or investigators and run in Portugal.Material and Methods: Clinical trials with Portuguese institutions as sponsor or recruiting centers, and registered in four clinical trial registries, in the last 14 years, were assessed. Publications of completed trials, from both the initiative of the industry and investigatorswere screened and compared.Results: The percentage of published trials initiated by industry and investigators was similar (28.0%). However, the percentage of completed investigator-initiated trials (43.6%) was lower when compared to industry trials (69.7%). There was a higher percentage of Portuguese authorship in published investigator-initiated trials when compared with industry-initiated trials (47.1% vs 8.5%, respectively). Moreover, industry-initiated trials with Portuguese authors were published in journals with lower journal impact factor when compared with those published without authorship of Portuguese investigators. Oncology was the therapeutic area with the highest number of clinical trial registrations and publications. However, in publications with Portuguese authors, industry Initiated trials mainly focused on neurology while investigator-initiated trials had a higher number of papers in the fields of gastroenterology and infection diseases. Published trials with Portuguese authorship, initiated by the industry or investigators, also targeted different populations and had different purposes. In both cases, no significant differences were observed in terms of the journal impact factor or in the alignment of the published randomized trials with the respective reporting guidelines.Discussion: When compared with previous publications, this study showed an increasing trend in the number of clinical trials in Portugal, published within similar timeframes, after trial conclusion. Even though both industry and investigator trials are published within the standards for reporting trials, the low number of Portuguese authorships in industry publications might underline the need for invigorating these independent clinical trials in Portugal by capacitating and empowering national clinical research teams.Conclusion: This study confirmed that even though all registered trials had the involvement of Portuguese institutions as a recruiting center, not all the published trials had Portuguese investigators as authors, mainly those initiated by the industry.

Investigator initiated trials versus industry sponsored trials - translation of randomized controlled trials into clinical practice (IMPACT)

Background Healthcare decisions are ideally based on clinical trial results, published in study registries, as journal articles or summarized in secondary research articles. In this research project, we investigated the impact of academically and commercially sponsored clinical trials on medical practice by measuring the proportion of trials published and cited by systematic reviews and clinical guidelines. Methods We examined 691 multicenter, randomized controlled trials that started in 2005 or later and were completed by the end of 2016. To determine whether sponsorship/funding and place of conduct influence a trial’s impact, we created four sub-cohorts of investigator initiated trials (IITs) and industry sponsored trials (ISTs): 120 IITs and 171 ISTs with German contribution compared to 200 IITs and 200 ISTs without German contribution. We balanced the groups for study phase and place of conduct. German IITs were funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), or by another non-commercial research organization. All other trials were drawn from the German Clinical Trials Register or ClinicalTrials.gov. We investigated, to what extent study characteristics were associated with publication and impact using multivariable logistic regressions. Results For 80% of the 691 trials, results were published as result articles in a medical journal and/or study registry, 52% were cited by a systematic review, and 26% reached impact in a clinical guideline. Drug trials and larger trials were associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as a journal article while results of ISTs were more often published in study registries. International ISTs less often gained impact by inclusion in systematic reviews or guidelines than IITs. Conclusion An encouraging high proportion of the clinical trials were published, and a considerable proportion gained impact on clinical practice. However, there is still room for improvement. For publishing study results, study registries have become an alternative or complement to journal articles, especially for ISTs. IITs funded by governmental bodies in Germany reached an impact that is comparable to international IITs and ISTs.

Construction and Confirmatory Factor Analysis of Panoramic Quality Assessment Tool for Investigator-Initiated Trials

Introduction. Investigator initiated trials (IITs) are laid on the optimization and improvement of already existing therapies or treatment approaches and attempts to answer problems faced by clinicians in their daily practice. However, the quality assessment for conducting these sometimes complex studies is scarce of evidence. Our study aims at developing a handy quality assessment tool for IITs and providing investigators with resources to conduct their studies effectively. Furthermore, patient safety and data quality will also be kept as top priorities.Data and methods. The framework of the quality assessment tool was based on the literature studies and accepted guidelines and the Delphi method. Confirmatory factor analysis (CFA) is used to further evaluate the validity and feasibility of the conceptual quality assessment tool. Results. The panorama quality assessment tool for IITs contains four critical quality attributes, including progress, quality, regulation, scientificity, and 13 observed quality indexes. 272 IITs were collected, finally, 252 IITs were included in the validity and feasibility assessment. The majority of the studies (60.29%) were in Randomized Controlled Trial (RCT), and 41.18% of the studies were multi-center. In order to test for validity and feasibility of IITs quality assessment tool, CFA method was showed a fit for the model (CMIN/DF=1.868, GFI=0.916; CFI=0.936; TLI=0.919; RMSEA=0.063). Multiple types of studies of clinical studies, including RCT, prospective cohort study, retrospective, and real-world research fitted well in the tool by assessing their subject management, reasonable clinical research methods, and quality control methods. However, RCT ended with lower scores than prospective cohort study, retrospective and real-world research in enrollment progress (7.02 vs. 7.43, 9.63, 7.85, respectively). Conclusions. The panorama tool for overall quality assessment of IITs from this study combines the advantages of both qualitative and quantitative recognized evaluation indexes, which are further validated by CFA. The panorama evaluation tool can timely and dynamically find errors, take actions to prevent major bias. It is hoped that this framework can provide project management departments with resources for effective and dynamic management of their research and avoid waste of resources, as well as a manner to improve the quality of IIT in the future.

Overview of Cellular Immunotherapies within Transfusion Medicine for the Treatment of Malignant Diseases

Over the years, transfusion medicine has developed into a broad, multidisciplinary field that covers different clinical patient services such as apheresis technology and the development of stem cell transplantation. Recently, the discipline has found a niche in development and production of advanced therapy medicinal products (ATMPs) for immunotherapy and regenerative medicine purposes. In clinical trials, cell-based immunotherapies have shown encouraging results in the treatment of multiple cancers and autoimmune diseases. However, there are many parameters such as safety, a high level of specificity, and long-lasting efficacy that still need to be optimized to maximize the potential of cell-based immunotherapies. Thus, only a few have gained FDA approval, while the majority of them are studied in the context of investigator-initiated trials (IITs), where modern, academically oriented transfusion centers can play an important role. In this review, we summarize existing and contemporary cellular immunotherapies, which are already a part of modern transfusion medicine or are likely to become so in the future.

Impact of Investigator Initiated Trials and Industry Sponsored Trials on Medical Practice (Impact): Results of a Cohort Study

BackgroundDecisions in healthcare are ideally made on basis of the results of clinical trials, published in study registries, as primary journal articles or summarized in secondary research articles. It is still unclear, whether and to what extent public and commercial expenses invested in clinical trials pays out in a way that their findings have an impact on publication output and medical practice.MethodsThe aim of this project was to examine the lifecycle of clinical trials from their registration to their publication and citation in secondary research articles by determining the proportion of trials that were published and were included in systematic review and clinical guidelines. We set-up a cohort of randomized controlled trials (n=691). We created and compared four sub-cohorts of investigator initiated trials (IITs) and industry sponsor trials (ISTs) with and without German contribution. For each trial, we searched for corresponding publications and citing systematic reviews and clinical guidelines.Additionally, we investigated what study characteristics are associated with publication and impact by using multivariable logistic regressions. ResultsOf the 691 trials, 576 (83%) were published as method article or result article in a medical journal and/or the trial results were made available in study registries; results were available for 555 (80%) of the trials. More than half (52%) of the trials were cited by a systematic review and about a quarter (26%) reached impact in a clinical guideline. Drug trials and larger trials are associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as journal article, results of ISTs more often in study registries. International ISTs gain less often impact by inclusion in systematic reviews or guidelines than publicly sponsored trials.ConclusionA considerable proportion of clinical trials investigated was published and had an impact on clinical practice, whereas the proportions depend on specific study characteristic. Study registries are an important alternative or complement to journal articles for publishing study results. There is still a need to improve the transfer of knowledge generated in clinical research into practice.

Impact of investigator initiated trials and industry sponsored trials on medical practice (IMPACT): rationale and study design

Background The German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF) initiated large research programs to foster high quality clinical research in the academic area. These investigator initiated trials (IITs) cover important areas of medical research and often go beyond the scope of industry sponsored trials (ISTs). The purpose of this project was to understand to what extent results of randomized controlled IITs and ISTs have an impact on medical practice, measured by their availability for decisions in healthcare and their implementation in clinical practice. We aimed to determine study characteristics influencing a trial’s impact such as type of sponsor and place of conduct. In this article, we describe the rationale and design of this project and present the characteristics of the trials included in our study cohort. Methods The research impact of the following sub-cohorts was compared: German IITs (funded by DFG and BMBF or by other German non-commercial organizations), international IITs (without German contribution), German ISTs, and international ISTs. Trials included were drawn from the DFG−/BMBF-Websites, the German Clinical Trials Register, and from ClinicalTrials.gov. Research impact was measured as follows: 1) proportion of published trials, 2) time to publication, 3) proportion of publications appropriately indexed in biomedical databases, 4) proportion of openly accessible publications, 5) broadness of publication’s target group, 6) citation of publications by systematic reviews or meta-analyses, and 7) appearance of publications or citing systematic reviews or meta-analyses in clinical practice guidelines. We also aimed to identify study characteristics associated with the impact of trials. Results We included 691 trials: 120 German IITs, 200 International IITs, 171 German ISTs and 200 International ISTs. The median number of participants was 150, 30% were international trials and 70% national trials, 48% drug-trials and 52% non-drug trials. Overall, 72% of the trials had one pre-defined primary endpoint, 28% two or more (max. 36). Conclusions The results of this project deepen our understanding of the impact of biomedical research on clinical practice and healthcare policy, add important insights for the efficient allocation of scarce research resources and may facilitate providing accountability to the different stakeholders involved.

Impact of investigator initiated trials and industry sponsored trials on medical practice (IMPACT): Rationale and study design

Background: The German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF) initiated large research programs to foster high quality clinical research in the academic area. These investigator initiated trials (IITs) cover important areas of medical research and often go beyond the scope of industry sponsored trials (ISTs). The purpose of this project was to understand to what extent results of randomized controlled IITs and ISTs have an impact on medical practice, measured by their availability for decisions in healthcare and their implementation in clinical practice. We aimed to determine study characteristics influencing a trial’s impact such as type of sponsor and place of conduct. In this article, we describe the rationale and design of this project and present the characteristics of the trials included in our study cohort. Methods: The research impact of the following sub-cohorts was compared: German IITs (funded by DFG and BMBF or by other German non-commercial organizations), international IITs (without German contribution), German ISTs, and international ISTs. Trials included were drawn from the DFG-/BMBF-Websites, the German Clinical Trials Register, and from ClinicalTrials.gov. Research impact was measured as follows: 1) proportion of published trials, 2) time to publication, 3) proportion of publications appropriately indexed in biomedical databases, 4) proportion of openly accessible publications, 5) broadness of publication’s target group, 6) citation of publications by systematic reviews or meta-analyses, and 7) appearance of publications or citing systematic reviews or meta-analyses in clinical practice guidelines. We also aimed to identify study characteristics associated with the impact of trials.Results: We included 691 trials: 120 German IITs, 200 International IITs, 171 German ISTs and 200 International ISTs. The median number of participants was 150, 30% were international trials and 70% national trials, 48% drug-trials and 52% non-drug trials. Overall, 72% of the trials had one pre-defined primary endpoint, 28% two or more (max. 36).Conclusions: The results of this project deepen our understanding of the impact of biomedical research on clinical practice and healthcare policy, add important insights for the efficient allocation of scarce research resources and may facilitate providing accountability to the different stakeholders involved.