The Survival and Financial Benefit of Investigator-Initiated Trials Conducted by Korean Cancer Study Group.

Purpose: The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods: We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results: From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from 6 available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion: Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.

Study on hospital exemption clause of advanced therapy medicinal products in EU and its enlightenment to China / 中国药房

OBJECTIVE To study the hospital exemption clause of advanced therapy medicinal products in the EU， and to provide policy recommendations for improving the regulatory system of cell and gene therapy （CGT） products in China. METHODS Through literature review and investigation of the official websites of EU member states， this study compared the differences in the application and implementation of the hospital exemption clause among member states from the perspectives of “non-conventional” definition， manufacturing standards， and pharmacovigilance requirements； the potential issues of hospital exemption clauses in practice were analyzed to propose policy recommendations based on the regulatory status of CGT in China. RESULTS & CONCLUSIONS EU has provided patients with rare diseases， who lack effective treatment or better therapy plans， with the opportunity to obtain new treatments through the hospital exemption clause， which has effectively improved the accessibility of medicines for patients. However， there still are certain disparities in the provisions of hospital exemption clause among EU member states. For instance， some member states have not explicitly defined “unconventional” circumstances； each member state has different requirements regarding production quality standards and pharmacovigilance requirement. Additionally， in the practical implementation of hospital exemption clause， issues such as poor transparency of information and a lack of certain restrictive conditions persist. Therefore， considering the current landscape and regulation of China’s CGT， it is recommended that China explore the clinical translational application of low-risk CGT in “unconventional” situations， strengthen the management of clinical translational application in terms of production quality standards and pharmacovigilance requirement. At the same time， it is necessary to further standardize the investigator initiated trials， and pay attention to the balance between clinical application and drug registration and marketing， thereby guiding the sustained and healthy development of China’s CGT.

Study on hospital exemption clause of advanced therapy medicinal products in EU and its enlightenment to China / 中国药房

OBJECTIVE To study the hospital exemption clause of advanced therapy medicinal products in the EU， and to provide policy recommendations for improving the regulatory system of cell and gene therapy （CGT） products in China. METHODS Through literature review and investigation of the official websites of EU member states， this study compared the differences in the application and implementation of the hospital exemption clause among member states from the perspectives of “non-conventional” definition， manufacturing standards， and pharmacovigilance requirements； the potential issues of hospital exemption clauses in practice were analyzed to propose policy recommendations based on the regulatory status of CGT in China. RESULTS & CONCLUSIONS EU has provided patients with rare diseases， who lack effective treatment or better therapy plans， with the opportunity to obtain new treatments through the hospital exemption clause， which has effectively improved the accessibility of medicines for patients. However， there still are certain disparities in the provisions of hospital exemption clause among EU member states. For instance， some member states have not explicitly defined “unconventional” circumstances； each member state has different requirements regarding production quality standards and pharmacovigilance requirement. Additionally， in the practical implementation of hospital exemption clause， issues such as poor transparency of information and a lack of certain restrictive conditions persist. Therefore， considering the current landscape and regulation of China’s CGT， it is recommended that China explore the clinical translational application of low-risk CGT in “unconventional” situations， strengthen the management of clinical translational application in terms of production quality standards and pharmacovigilance requirement. At the same time， it is necessary to further standardize the investigator initiated trials， and pay attention to the balance between clinical application and drug registration and marketing， thereby guiding the sustained and healthy development of China’s CGT.

The landscape of investigator-initiated oncology trials conducted in mainland China during the past decade (2010-2019).

The number of clinical trials conducted in mainland China, including investigator-initiated trials (IITs), has increased rapidly in recent years. However, there are few data on the characteristics of cancer-related IITs. We performed a comprehensive analysis of the landscape of cancer-related IITs in mainland China in the past decade. All cancer-related IITs registered on two clinical trial registries in the United States (www.clinicaltrials.gov, CT.gov) and mainland China (www.chictr.org.cn, ChiCTR) from 2010 to 2019 were identified. IITs were reviewed manually to validate classification, subcategorized by cancer type, and stratified by design characteristics to facilitate comparison across cancer types and with other specialties. A total of 8199 cancer-related IITs were identified. The number of trials registered annually increased over time, especially in the last 5 years. Although interventional studies were predominant, randomized double-blind studies accounted for only 8% of IITs. In the past decade, the trend for interventional studies conducted with different drugs increased year on year, although the increase in hormonal therapy IITs was not significant. Additionally, cancer-related IITs were unevenly geographically distributed, with half concentrated in the economically developed cities Shanghai, Beijing, and Guangdong. We also found an increase in registration before participant enrollment (64.9% for trials in conducted in 2015-2019 vs. 40.2% in 2010-2014, p < 0.001) and data monitoring committee use (44.5% vs. 40.0%, p = 0.001) and a decrease in randomization (51.5% vs. 62.7%, p < 0.001) and funding (36.4% vs. 56.3%, p < 0.001) between these periods. We also observed changes in intervention type (decrease in cytotoxic drug therapy [34.8% vs. 48.9%, p < 0.001]; increase in targeted therapy [17.8% vs. 14.2%, p = 0.004], immune checkpoint inhibitor therapy [6.6% vs. 0.0%, p < 0.001], and immune cell therapy [9.6% vs. 4.5%, p < 0.001]). Details of cancer-related IITs conducted during the past decade illustrate the merits of oncology research in mainland China. Although the increased quantity of IITs is encouraging, limitations remain regarding the quality of clinical trials, regional imbalances, and funding allocation.

The Development of Investigator-Initiated Clinical Trials in Surgical Oncology.

Investigator-initiated trials (IITs) are designed by principal investigators who identify important, unaddressed clinical gaps and opportunities to answer these questions through clinical trials. Surgical oncologists are poised to lead IITs due to their multidisciplinary clinical practice and substantial research background. The process of developing, organizing, and implementing IITs is multifaceted and involves important steps including (but not limited to) navigating regulatory requirements, obtaining funding, and meeting enrollment targets. Here, the authors explore the steps, methodology, and barriers of IIT development by surgical oncologists and highlight the importance of IITs in oncology.

Racial Disparities in Clinical Outcomes on Investigator-Initiated Breast Cancer Clinical Trials at an Urban Medical Center.

BACKGROUND: Black women are 40% more likely to die of breast cancer compared to White women. Inadequate representation of Black patients in clinical trials may contribute to health care inequity. We aimed to assess breast cancer clinical outcomes in Non-Hispanic Black (Black) versus Non-Hispanic White (White) women with metastatic breast cancer (MBC) enrolled on investigator-initiated clinical trials at Winship Cancer Institute at Emory University, given the significant number of patients from underrepresented minority groups seen at Winship. MATERIALS AND METHODS: Black and White women with MBC on investigator-initiated trials at Emory between 2009 and 2019 were retrospectively evaluated. Univariate analyses and multiple logistic regression models were used to assess clinical response and treatment toxicities. Differences in overall survival between groups was assessed using quantile analysis. RESULTS: Sixty-two women with MBC were included (66% White vs. 34% Black). Black patients had less clinical benefit from the trial therapy as only 57% had partial response or stable disease as best response compared to 78% of White women (P = .09). Quantile analysis showed significant difference in mean survival between Whites and Blacks by the end of follow up (64 vs. 38 months). There were no significant differences in toxicities between groups. CONCLUSION: Participation rates of Black women with MBC on investigator-initiated clinical trials at an urban cancer center were higher compared to key national trials. Black women had worse treatment response and survival. These results reinforce the need for assessment of tumor differences by ancestry and continued improvement in minority representation on clinical trials.

Panoramic quality assessment tool for investigator initiated trials.

Objectives: Quality can be a challenge for Investigator initiated trials (IITs) since these trials are scarcely overseen by a sponsor or monitoring team. Therefore, quality assessment for departments managing clinical research grants program is important and urgently needed. Our study aims at developing a handy quality assessment tool for IITs that can be applied by both departments and project teams. Methods: The framework of the quality assessment tool was developed based on the literature studies, accepted guidelines and the Delphi method. A total of 272 ongoing IITs funded by Shanghai non-profit organizations in 2015 and 2016 were used to extract quality indexes. Confirmatory factor analysis (CFA) was used to further evaluate the validity and feasibility of the conceptual quality assessment tool. Results: The tool consisted of 4 critical quality attributes, including progress, quality, regulation, scientificity, and 13 observed quality indexes. A total of 257 IITs were included in the validity and feasibility assessment. The majority (60.29%) were Randomized Controlled Trial (RCT), and 41.18% were multi-center studies. In order to test the validity and feasibility of IITs quality assessment tool, CFA showed that the model fit the data adequately. (CMIN/DF = 1.868, GFI = 0.916; CFI = 0.936; TLI = 0.919; RMSEA = 0.063; SRMR = 0.076). Different types of clinical studies fit well in the tool. However, RCT scored lower than prospective cohort and retrospective study in enrollment progress (7.02 vs. 7.43, 9.63, respectively). Conclusion: This study established a panoramic quality assessment tool based on the Delphi method and CFA, and the feasibility and effectiveness of the tool were verified through clinical research examples. The use of this tool can help project management departments effectively and dynamically manage research projects, rationally allocate resources, and ensure the quality of IITs.

Activation of Investigator-Initiated Clinical Trials with a Pharmaceutical for Cancer Patients before and after Post-Millennial Changes of Regulations in Germany and Europe.

Shortly after the beginning of the year 2000, multiple legal changes with impacts on the regulatory framework of clinical trials became effective almost simultaneously. They included the European Union (EU) Clinical Trial Directive (CTD) 2001/20 followed by major changes in national drug laws, the change in the legal status of German University Hospitals (1998), and a new disease-related groups (DRG)-based reimbursement system for hospitals in Germany (2000). Together, these changes created enormous bureaucratic and financial inhibition of activation and conduct of academic investigator-initiated clinical trials (IIT). Examples for activating clinical trials in oncology before and after 2004 are outlined and discussed, focussing on extended time frames, the establishment of centralized responsibility structures and the exploding financial consequences. In addition, the evolution of trial numbers and the distribution of trial initiators between "commercial" and "academic" over time are discussed together with the occurrence of clinical registries. At the same time, progress in molecular biology led to a plethora of new targets for effective pharmacological therapy of life-threatening diseases such as cancer, and the overall number of clinical trials has not decreased. Yet, judging the regulatory and administrative hurdles between scientific study design and first-patient on trial before and after 2004 and weighing these against the lack of evidence that this regulation has achieved its goal to enhance patient safety and trial quality, the necessity to completely overhaul this CTD becomes obvious. A main goal of such an initiative should be to minimize bureaucracy. For the specific situation in Germany, relocation of responsibility and freedom to operate in University Hospitals and Medical Faculties back to the physician-scientists and reduction in interference by legal divisions should be a goal as well as increasing the public financial support for IITs.

Discussions on the quality control system of investigator initiated trials in the new circumstances / 中华医院管理杂志

China is stepping up its standardized management of investigator initiated trials(IIT)carried out by medical and health institutions, spotlighting the establishment and improvement of the quality control system of IIT projects than ever before. The authors retrieved official websites of clinical research related units of medical institutions and research institutes at home and abroad, and by means of literature review analyzed the current quality management of IIT projects at home and abroad. They found such setbacks as lack of quality management standards and norms, imperfect quality control mechanism, poor awareness of quality risk, insufficient quality supervision and poor quality control ability of clinical researchers. Based on the above, the paper made the following recommendations for building an IIT project quality control system in China: developing quality management standards and norms, setting up a systematic quality control mechanism(i.e., exploring a three-level quality control mode composed of the project team/department-hospital-national supervision institution/peer review expert team, and implementing the whole process quality control mechanism), strengthening policy guidance and system construction, and strengthening the standardized training of clinical researchers.

Discussions on risk-based quality management of investigator initiated trials / 中华医院管理杂志

Effective supervision of the clinical research management department can guarantee and improve the quality of the investigator initiated trials(IIT). The authors analyzed relevant clinical research regulations and literature and summarized the current situation of risk-based IIT project process quality management. On such basis, they determined the risk-based IIT project process quality management method in combination with the previous research of the research group.From 2021 to 2022, this method was used to implement process quality management for 353 IIT projects in Shanghai′s tertiary hospitals. More than 3 000 risk points were identified through centralized supervision, and then on-site supervision was carried out to correct the problems found. As proven by the results, the method could find existing problems in time and define the risk level of the project, and also formulate an individualized risk supervision plan accordingly, so as to effectively ensure the data reliability and scientific results. It is suggested that the clinical research management department implement risk based management for the whole process of IIT projects, increase funding and staffing, and implement hierarchical management for the projects by research types, so as to promote the sustainable development of IITs.

Assuring data quality in investigator-initiated trials in dutch hospitals: Balancing between mentoring and monitoring.

The complexity of regulations governing investigator-initiated trials (IITs) places a great burden on hospitals. Consequently, many hospitals seek to alleviate regulatory pressures by seeking an alternative quality management system (QMS). This paper takes the Netherlands as a case. To investigate how QMSs for IITs are organized in Dutch hospitals, we adopted the theoretical concepts of mentoring and monitoring in a mixed methods study in the period 2014-2018. In clinical practice and international guidelines, monitoring is seen as the standard quality assurance for ongoing trials. However, hospitals have implemented monitoring programs that resemble mentoring. The contrast between these ideal types is less pronounced in practice as both combine elements of compliance and feedback for learning in practice. In a monitoring setting, learning is one-way, from monitor to researcher; whereas mentoring focuses on mutual support and learning. To tackle problems in each system, the authority of the Board of Directors (BoD) and the BoD's relationship with staff members are crucial. We discuss the challenges that BoD and staff face in keeping an integrated view of the various components of QMSs.

Strategies and measures for improving the quality of Investigator-Initiated Trials / 中华医学科研管理杂志

Objective:To explored how medical and health institutions can improve the quality of Investigator-Initiated Trials(IIT).Methods:Strategies and measures were proposed to ensure the quality of IIT based on the combination of related literature review and IIT management experiences analysis.Results:Institutions can carry out following measurements to improve the quality of IIT, which include setting up tailored IIT management department, establish centralized management system; conducting systematic regulatory and clinical research methodology trainings; develop effective quality control system and quality assessment index, applying electronic information system and platform to optimize the management.Conclusions:Strengthen the standardized management is an effective strategy to improve the quality of IIT in medical and health institutions.

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.

A meta-research study revealed several challenges in obtaining placebos for investigator-initiated drug trials.

OBJECTIVES: To systematically assess the kind of placebos used in investigator-initiated randomized controlled trials (RCTs), from where they are obtained, and the hurdles that exist in obtaining them. STUDY DESIGN AND SETTING: PubMed was searched for recently published noncommercial, placebo-controlled randomized drug trials. Corresponding authors were invited to participate in an online survey. RESULTS: From 423 eligible articles, 109 (26%) corresponding authors (partially) participated. Twenty-one of 102 (21%) authors reported that the placebos used were not matching (correctly labeled in only one publication). The main sources in obtaining placebos were hospital pharmacies (32 of 107; 30%) and the manufacturer of the study drug (28 of 107; 26%). RCTs with a hypothesis in the interest of the manufacturer of the study drug were more likely to have obtained placebos from the drug manufacturer (18 of 49; 37% vs. 5 of 29; 17%). Median costs for placebos and packaging were US$ 58,286 (IQR US$ 2,428- US$ 160,770; n = 24), accounting for a median of 10.3% of the overall trial budget. CONCLUSION: Although using matching placebos is widely accepted as a basic practice in RCTs, there seems to be no standard source to acquire them. Obtaining placebos requires substantial resources, and using nonmatching placebos is common.

Climbing the steps of the evidence-based medicine pyramid: highlights from Annals of Nuclear Medicine 2019.

We aimed to provide an overview on research path in nuclear medicine climbing the steps of the Evidence-Based Medicine (EBM) pyramid using review of 14 subjectively selected papers out of 111 published in the Annals of Nuclear Medicine during January-December 2019. Following the structure of the EBM hierarchy, we chose at least one study for each step of the pyramid from the basis (pre-clinical research, expert opinion, case report and case series), to the middle (case-control and cohort studies, randomised controlled trials), towards the top (meta-analyses and systematic reviews). Additionally, we collected information on the promoter of each included study: investigator-initiated trials (IITs) vs industry-sponsored trials (ISTs). We found that pre-clinical studies are primarily focused on the development of novel molecular targets in cancer, with promising results. At the same time, clinical investigations deal with cardiological, neurological, infectious and oncological applications using both SPECT and PET modalities. Additionally, radionuclide therapy gained interest and is experiencing comprehensive clinical implementation. Our overview confirms the current central role of IITs as compared with ISTs. Challenges and future directions in Nuclear Medicine research are discussed.

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.

Analysis and reflections on construction of clinical research methodology support system by IITs: Demonstration examples from construction of MACRO in Shanghai Jiao Tong University School of Medicine / 中华医学科研管理杂志

Objective To improve clinical research capability and quality,this study aims to explore the methodological support system of Investigator Initiated Trials (IITs).Methods By comparing the clinical research supporting system between commercial and academic organization at home and abroad,this study summarized their characteristics and make systematic analysis combined with IITs.Results Compared with international level,there is an urgent need to improve of domestic,professional support for clinical research.Academic clinical research supporting academic system could better satisfy the requirement of IITs in China.Taking Shanghai Jiao Tong University School of Medicine as an example,this paper introduces the a collaborative construction model,namely Multiple-center Academic Clinical Research Organization (MACRO),based on two levels of clinical research institutes in university and affiliated hospitals.At universities level,we focused on development of clinical research,top-level study design,clinical research methodology,clinical research professionals and standardized clinical research platform.At hospitals level,project process management can be emphasized,and which will be the main implementation content to build an applied clinical research technology center in MACRO.Conclusions With the construction of MACRO,the functional module paradigms of academic clinical research centers in university can be effectively linked to affiliated hospitals.This will be conducive for establishing collaborative support system,which is centered on academic research and complementary functions with multiple centers,improving full-time technical team and further enhancing the scientific validity and research quality of IITs.

Quality evaluation of Investigator-Initiated Trials at the early approval stage / 中华医学科研管理杂志

Objective With the fast development of Investigator-Initiated Trials (IIT),more and more resources from the national and local governments,universities and hospitals were invested.It is important to clarify the content and methodologies of quality evaluation of the IITs at the early approval stage to assure more complete and systematic quality assessment,improve resource allocation,enhance the research ability,as well as the protection of human subject.Methods This article summarized the content and related safeguarding measures of quality assessment during the early stage of project setup.Discussed relative practice and experiences of our center.Results The contents of quality evaluation include research topic,study protocol,research team and qualifications,quality assurance plan and risk management.The organizing work and attention of the research administrative department,qualified departments and experts,as well as information platform are the required safeguarding measures for effective assessment.Conclusions Quality evaluation of IITs at the early approval stage is critical segment of study quality assurance.More attention should be paid to make every effort counts.

[From the national competence network for viral hepatitis (HepNet) emerged the German Liver Foundation (Deutsche Leberstiftung)]. / Vom Kompetenznetz Hepatitis (HepNet) zur Deutschen Leberstiftung.

The competence network for viral hepatitis (HepNet) was founded in 2002 with funding from the German government and has influenced the research on viral hepatitis in Germany. HepNet collaborator sites have been involved in numerous national and international investigator-initiated, as well as industry-sponsored, phase 1-3 studies. Within the HepNet Study-House, many groundbreaking investor-initiated trials have been completed and are still ongoing. For example, the acute hepatitis C trials and trials on chronic hepatitis D (delta), which led to therapy optimization. Continuation of the competence network on viral hepatitis has been achieved by the foundation of the German Liver Foundation, which has been an external cooperation partner of the German Center for Infection Research (DZIF) for two years. The well-established HepNet Study-House acts here as the clinical trial platform for all DZIF hepatitis trials.