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Protocol design trends and their effect on clinical trial performance

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... In 2016, there were 85 ongoing phase II or III trials for AML for adults listed in the EU Clinical Trials Register for Germany (236 trials for whole Europe). Clinical trial documentation itself is typically extensive and time-consuming [5]. In clinical trials, more than 1,000 items such as laboratory values, vital signs and diagnostic tests are collected per patient [6]. ...
... In clinical trials, more than 1,000 items such as laboratory values, vital signs and diagnostic tests are collected per patient [6]. The number of pages in case-report-forms (CRFs) per trial has risen from 55 to 180 during the last years [5]. Study assistants are employed to re-enter routine data into study CRFs manually, although automatic comparison and transformation is technically possible with minor limitations [7]. ...
... The reuse potential of information is generally higher if the original data is documented in a structured way [10,11]. The redundancy level of documentation within different documentation contexts is high [5]. Even the German Ministry of Health already recognized that large amounts of data are gathered redundantly and that cost-benefit-analyses are recommendable [12]. ...
Article
Background For cancer domains such as acute myeloid leukemia (AML), a large set of data elements is obtained from different institutions with heterogeneous data definitions within one patient course. The lack of clinical data harmonization impedes cross-institutional electronic data exchange and future meta-analyses. Objective This study aimed to identify and harmonize a semantic core of common data elements (CDEs) in clinical routine and research documentation, based on a systematic metadata analysis of existing documentation models. Methods Lists of relevant data items were collected and reviewed by hematologists from two university hospitals regarding routine documentation and several case report forms of clinical trials for AML. In addition, existing registries and international recommendations were included. Data items were coded to medical concepts via the Unified Medical Language System (UMLS) by a physician and reviewed by another physician. On the basis of the coded concepts, the data sources were analyzed for concept overlaps and identification of most frequent concepts. The most frequent concepts were then implemented as data elements in the standardized format of the Operational Data Model by the Clinical Data Interchange Standards Consortium. Results A total of 3265 medical concepts were identified, of which 1414 were unique. Among the 1414 unique medical concepts, the 50 most frequent ones cover 26.98% of all concept occurrences within the collected AML documentation. The top 100 concepts represent 39.48% of all concepts’ occurrences. Implementation of CDEs is available on a European research infrastructure and can be downloaded in different formats for reuse in different electronic data capture systems. Conclusions Information management is a complex process for research-intense disease entities as AML that is associated with a large set of lab-based diagnostics and different treatment options. Our systematic UMLS-based analysis revealed the existence of a core data set and an exemplary reusable implementation for harmonized data capture is available on an established metadata repository.
... This effort in documentation is even extended by register and trial documentation. Clinical trial documentation itself is typically extensive and time-consuming [12]. In clinical trials, more than 1,000 items such as laboratory values, vital signs and diagnostic tests are collected per patient [13]. ...
... In clinical trials, more than 1,000 items such as laboratory values, vital signs and diagnostic tests are collected per patient [13]. The number of pages in case-report-forms (CRFs) per trial has risen from 55 to 180 during the last years [12]. The redundancy level of documentation within different documentation contexts is high [12]. ...
... The number of pages in case-report-forms (CRFs) per trial has risen from 55 to 180 during the last years [12]. The redundancy level of documentation within different documentation contexts is high [12]. In addition, the mode of documentation is still different. ...
Preprint
BACKGROUND For cancer domains as Acute Myeloid Leukemia (AML), a large set of data elements is obtained from different institutions with heterogeneous data definitions within one patient course. The lack of clinical data harmonization impedes cross-institutional electronic data exchange and future meta-analyses. OBJECTIVE To identify and harmonize a semantic core of common data elements (CDEs) in clinical routine and research documentation based on a systematic metadata analysis of existing documentation models. METHODS Lists of relevant data items were collected and reviewed by hematologists from two university hospitals regarding routine documentation and several case report forms of clinical trials for AML. In addition, existing registries and international recommendations were included. Data items were coded to medical concepts via the Unified Medical Language System and then systematically analyzed for concept overlaps and identification of most frequent concepts. The most frequent concepts were then implemented as data elements in the standardized format Operational Data Model by the Clinical Data Interchange Standards Consortium. RESULTS 3265 medical concepts were identified of which 1414 were unique. Among 1414 unique medical concepts, the 50 most frequent cover 27.0% percent of all concept occurrences within the collected AML documentation. The top 100 concepts represent 39.5% of all concepts occurrences. Implementation of common data elements is available on a European research infrastructure and can be downloaded in different formats for reuse in different electronic data capture systems. CONCLUSIONS Information management is a complex process for research-intense disease entities as AML that is associated with a large set of lab-based diagnostics and different treatment options. Our systematic UMLS-based analysis revealed the existence of a core data set and an exemplary reusable implementation for harmonized data capture is available on an established metadata repository.
... Cognizant of the negative impact of an overly complex protocol design [4,5], STEADY PD III SC worked to reduce the stringency of eligibility criteria and lessen participant burden while maintaining a careful balance between investigative and scientific rigor. These objectives were accomplished through the following protocol modifications: 1) reducing the length of time before projected initiation of symptomatic therapy (ST) from 6 months to 3 months; 2) extending the duration of participant follow up to 36 months; and 3) using change in total UPDRS score in the medications' ON state, if ST had been initiated, as the primary outcome measure. ...
... Clinical trial complexity is an issue that has been on the rise over the past 20 years. Research by the Tuft's Center for the Study of Drug Development found that in this time, the average number of inclusion criteria have increased threefold and the number of unique procedures per protocol have increased by 6.5% [4]. This growing level of complexity has negatively impacted recruitment, resulting in a 53% increase in the times between study initiation and completion, and a 16% reduction in enrollment rates [4]. ...
... Research by the Tuft's Center for the Study of Drug Development found that in this time, the average number of inclusion criteria have increased threefold and the number of unique procedures per protocol have increased by 6.5% [4]. This growing level of complexity has negatively impacted recruitment, resulting in a 53% increase in the times between study initiation and completion, and a 16% reduction in enrollment rates [4]. The authors posit that this trend is attributable to a shift in focus to chronic diseases, where clinical endpoints are difficult to measure and the target population for recruitment is highly specific. ...
Article
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Background Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson’s disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. Objective This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. Methods STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. Results A total of 336 individuals, including 34 minorities, were enrolled within 12 months – 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). Conclusions STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research.
... Stakeholders in the clinical research enterprise have become keenly interested in improving public and patient engagement in clinical trials 1 for reasons that include ensuring that the most relevant and clinically meaningful outcomes are being assessed and improving study volunteer recruitment and retention rates. 2 Increasing protocol design complexity during the past 2 decades has had an adverse effect on the cost and length of the drug-development process, placed undue burden on clinical research professionals administering clinical trial procedures, 3,4 and impeded the willingness of study volunteers to be screened for and remain in a study through its completion. 4 Among initiatives being piloted and implemented are the following: (1) US Food and Drug Administration and European Medicines Agency meetings with patients and their families to learn about direct experiences managing select diseases; (2) pharmaceutical and biotechnology company collaborations with patient advocacy groups and social media patient communities; (3) the use of patient advisory board panels to solicit input on draft protocol designs; (4) the deployment of telemedicine and home nursing networks to improve participation convenience; and (5) the return of clinical trial results summaries in plain language to study volunteers. ...
... Participating in a clinical trial is burdensome for patients, whose daily routines might be disrupted by the need to return to an investigative site multiple times for study-related procedures and on-or off-site laboratory work, particularly because protocols have become increasingly complex. Soliciting feedback from patients and investigative site staff to optimize protocol designs should help reduce participation burden.3 Greater adoption of convenience-enhancing initiatives andJAMA Network Open | Global HealthGlobal Public Attitudes About Clinical Research and Patient Experiences With Clinical Trials technologies may also be important in retaining clinical trial enrollees. ...
Article
Full-text available
Importance Effective, continuous improvement in patient engagement depends on an intimate understanding of public and patient perceptions and experiences in clinical research. Objectives To identify the views of clinical trial participants and nonparticipants and characterize trends in these views over time. Design, Setting, and Participants In this survey study, a questionnaire was administered online from May 8 to July 24, 2017, by the Center for Information and Study on Clinical Research Participation (CISCRP), and findings were compared with previous studies conducted in 2013 and 2015. The 2017 sample included responses from 12 427 individuals from 68 countries and represents a 10% participation rate. Similar to international assessments conducted by the CISCRP and other organizations, this study drew responses from a convenience sample; any adult older than 18 years who received an email or had online access was eligible to participate. Main Outcomes and Measures Significant changes were observed in the perceptions and clinical trial experiences of the public and study volunteers compared with past CISCRP studies. Results A total of 12 427 individuals (mean [SD] age, 55 [15] years; 7355 [59.2%] female; 10 085 [81.2%] white), 2194 (17.7%) of whom had participated in previous clinical research studies, responded to the survey in 2017. Findings indicated a belief in the importance of clinical research, but limited understanding of the research process persists. In 2017, a total of 10 506 individuals (84.5%) perceived clinical research to be very important to the discovery and development of new medicines; however, 4079 of 6919 respondents (59.0%) were unable to name a place where studies were conducted. A total of 11 182 respondents (90.0%) believed that clinical research is generally safe; however, 5578 of 12 427 individuals (44.9%) reported that clinical trials are rarely considered as an option when discussing treatments or medications with their physician. Clinical trial participation was perceived as inconvenient and burdensome; in the latest survey, 1075 respondents (49.0%) expressed that their clinical trial participation disrupted their daily routine. Conclusions and Relevance The results of this study may provide a foundation from which to build meaningful and effective engagement with the public and patients and revealed roadblocks, including knowledge gaps among the public, limited physician involvement in discussing clinical trials as treatment options, and the inconveniences that patients encounter after they volunteer to participate. These findings may inform patient engagement strategies and tactics and ultimately help accelerate the drug-development process.
... Dies gilt gleichermaßen für kommerzielle Studien und Investigator initiated trials (IITs). Lediglich die Ein-/Ausschlusskriterien stehen öffentlich zur Verfügung [1] – und diese noch nicht einmal vollständig [2] –, die jedoch nur etwa 1% der CRFs umfassen [3]. Es werden zwar zunehmend Studienprotokolle publiziert, jedoch bisher meist ohne die eingesetzten CRFs. ...
... Für jede Studie bzw. jedes Informationssystem kann von einer Größenordnung von mindestens 100 [3] unterschiedlichen Dokumentationsformularen (in klinischen Arbeitsplatzsystemen oft mehr als 1.000) ausgegangen werden. ...
Article
Full-text available
[english] Currently, most of the documentation forms and item catalogs in healthcare are not accessible to the public. This applies both to clinical information systems and case report forms (CRFs) from studies. Open access to medical documentation forms could substantially improve information systems in healthcare and networked medical research. Therefore it should be implemented, wherever possible from a legal point of view.
... Such complex protocols impact the site performance. [4] The patient enrolment rates (i.e. the percentage of patients randomized following screening) dropped from 75% in 1999-2002 to 59% in 2003-06, and the study completion rates for patients fell from 69% to 48%. ...
... During the time period, India became a clinical trial destination, the clinical trial protocols have become more complex, demanding, and burdensome for both sites and patients. Between 1999 and 2005, [4] the average number of inclusion criteria has increased threefold. The average number of procedures grew annually by 6.5%, reaching a median number of 35 procedures in 2005. ...
... Data models in clinical studies are increasingly complex. Since introduction of the European Clinical Trials Directive (2001/20/ EC), the average length of CRFs increased from 55 pages (1999)(2000)(2001)(2002) to 180 pages (2003)(2004)(2005)(2006) per trial [1], associated with major additional costs [2]. Under the assumption that a typical CRF page contains 20-50 items, this corresponds to 3600 to 9000 data items per trial. ...
... Currently, different tools are being applied for this task, in particular office tools like Microsoft Excel, EDC tools and statistics software. In clinical trials, CRFs are quite complex with 180 CRF pages on average [1]. Given this complexity of data models, the iterative nature of CRF design, and the need to synchronize different representations (office/EDC/statistics format), an automated method obviously can help to reduce manual, error-prone transformation work. ...
Article
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Design, execution and analysis of clinical studies involves several stakeholders with different professional backgrounds. Typically, principle investigators are familiar with standard office tools, data managers apply electronic data capture (EDC) systems and statisticians work with statistics software. Case report forms (CRFs) specify the data model of study subjects, evolve over time and consist of hundreds to thousands of data items per study. To avoid erroneous manual transformation work, a converting tool for different representations of study data models was designed. It can convert between office format, EDC and statistics format. In addition, it supports semantic annotations, which enable precise definitions for data items. A reference implementation is available as open source package ODMconverter at http://cran.r-project.org.
... The clinical trial protocols have become increasingly complex. [3] According to a study of over 10,000 protocols, Dr. Getz observed that between 1999 and 2005, the number of unique study procedures grew by 6.5% annually. During the same period, the average number of inclusion criteria increased nearly thrice. ...
... Dr Getz concluded that such a significant increase in the investigator site burden would adversely impact the site performance. [3] The other major factor is globalization of clinical trials. According to Glickman et al., since 2002, there has been a 15% annual growth in the number of active FDA-regulated investigators based outside the US. ...
Article
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Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials.
... While there are clear advantages in conducting clinical trials in these areas such as increased recruitment potential, lower costs, there are challenges such as variability in clinical practice, regulations, ethical processes and local guidelines. Global data in recent times has shown a much longer clinical trial cycle time in terms of patient recruitment rates, time from first patient first visit (FPFV) to last patient last visit (LPLV) and total recruitment.4 ...
... Site or Investigator level: This is actually the micro- feasibility – deciding whether to work with an investigator or not and identifying challenges and probable solutions. Given the challenges above, selecting the right site is of paramount importance.4 While country offices have greater responsibility in this case, study teams provide overall oversight and guidance. ...
Article
Conducting clinical trial feasibility is one of the first steps in clinical trial conduct. This process includes assessing internal and environmental capacity, alignment of the clinical trial in terms of study design, dose of investigational product, comparator, patient type, with the local environment and assessing potential of conducting clinical trial in a specific country. A robust feasibility also ensures a realistic assessment and capability to conduct the clinical trial. For local affiliates of pharmaceutical organizations, and contract research organizations, this is a precursor to study placement and influences the decision of study placement. This article provides details on different types of feasibilities, information which is to be included and relevance of each. The article also aims to provide practical hands-on suggestions to make feasibilities more realistic and informative.
... Pressure to reach treatment-naïve patient communities, identify less expensive though well-trained investigators, and support simultaneous international submissions drove more globally oriented protocol designs in the early 2000s [5,6]. During this decade, regulatory agency interest in quality by design principles and in improving risk evaluation and mitigation drove growth in the number of safety procedures and the volume of data collected in phase I and II protocol designs [7][8][9]. ...
Article
Background: Benchmark data characterizing protocol design practices and performance informs clinical trial design decisions and serves as important baseline measures for assessing protocol design behaviors and their impact during and post-pandemic. Methods: Tufts CSDD, in collaboration with a working group of 20 major and mid-sized pharmaceutical companies and CROs, gathered phase I-III data from protocols completed just prior to the start of the global pandemic. Results: Data for 187 protocols were analyzed to derive benchmarks overall and for two primary subgroups: oncology vs. non-oncology protocols and rare disease vs. non-rare disease protocols. The results show a continuing upward trend across all protocol design variables. Phase II and III protocols average more endpoints, eligibility criteria, protocol pages; investigative sites; countries and datapoints collected. Oncology and rare disease protocols' enrolled-to-completion rates are much lower, involve a much higher average number of countries and investigative sites, require more planned patient visits and generate considerably more clinical research data. As such, oncology and rare disease clinical trial cycle times are longer-most notably at time periods occurring after study startup and prior to database lock-due to intense patient recruitment and retention challenges. Conclusions: The results of this study present valuable design insights and comparative baseline measures. The implications of these results and the expected impact of decentralized clinical trials on protocol design practices and performance is discussed.
... It would be worthwhile to conduct a systematic review to compare these aspects pre-and post-GCP. There are no data to suggest that there has been an increase in quality; on the contrary, it has been suggested that increasing complexity in clinical trials (>200% rise in the number of CRF pages from 1999 to 2005) could have an adverse impact (25). There are also no data to indicate that research misconduct declined post-GCP; in fact, anecdotal reports suggest it may be increasing or at least not declining (26,27,28,29). ...
Article
GCP has become the gold-standard for clinical research; initiated as a guideline pertaining to new drug development, it became a law in many countries, extending its scope to include all research. GCP is an excellent document that outlines the responsibilities of stakeholders involved in clinical research. Widely acclaimed, and deservedly so, it is considered as the “go-to” document whenever questions arise during the conduct of a clinical trial. This article presents another narrative, one that has not been articulated so far. Irrespective of whether we consider GCP as a law or a guideline, it is viewed as an “official” document, without the overt realisation that this was actually an initiative of the pharmaceutical industry, the “masters of mankind”. While the stress on documentation and monitoring in GCP was justified, its over-interpretation led to increased costs of clinical trials, with the result that smaller companies find it difficult to conduct the already expensive trials. GCP as an idea is now so entrenched within the scientific community that the real aims which led to its birth and that can be mined from the ICH website, like the need for market expansion, have remained largely unnoticed and undocumented, and are being expressed here.
... II. RELATED WORK The traditional healthcare system gathers approximately 180 pages for each patient [9]. Nowadays, due to the electronic healthcare records systems doctors and medical practitioners keep the track of information related to the patient's health and offer access to the records through a centralized electronic system. ...
Preprint
Full-text available
Digital instruments play a vital role in our daily life. It is a routine to produce business papers, watch the news program, write articles and blogs, manage healthcare systems, to purchase online, to send messages and all this is processed by making observations and then manipulating, receiving and availing the diverse data. This electronic data provides the foundation of real time data. All this transmission of data needs to be secured. Security is essential for healthcare systems as the present one where the blood pressure recordings provided by the smart bracelet are sent to the user's mobile phone via Bluetooth. The bracelet monitors the pregnant women, but also other users who wish to have their blood pressure under control. The system's server analyses the recordings and announces the user, as well as the associated persons to the user in case of an emergency. The doctors, the medical staff, user and user's family and caregivers have access to the health recordings belonging to the monitored user. Security is a main feature of the electronic healthcare system based on the smart bracelet.
... The traditional healthcare system gathers approximately 180 pages for each patient [20]. Nowadays, due to the electronic healthcare records systems doctors and medical practitioners keep the track of information related to the patient's health and offer access to the records through a centralized electronic system. ...
Conference Paper
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Electronic healthcare devices are considerably more utilized as the time passes. Pregnant women who suffer from preeclampsia and the persons who have cardiac diseases can have their heart rate monitored through the use of a smart bracelet. The created bracelet sends the measured values towards the user's associated smart phone and then to the system's server. The server interprets the health parameters and alerts the associated relatives, caregivers and the doctor in case of an emergency by sending an SMS. On the system's forum the bracelet's user can write about the current health symptoms and the medical experience. Sentiment analysis is applied to determine if a critical situation has been described. In this case, an SMS alert is delivered to the user's doctor. This close connection between the patient and doctor upgrades the quality of life.
... II. RELATED WORK The traditional healthcare system gathers approximately 180 pages for each patient [9]. Nowadays, due to the electronic healthcare records systems doctors and medical practitioners keep the track of information related to the patient's health and offer access to the records through a centralized electronic system. ...
Conference Paper
Full-text available
Digital instruments play a vital role in our daily life. It is a routine to produce business papers, watch the news program, write articles and blogs, manage healthcare systems, to purchase online, to send messages and all this is processed by making observations and then manipulating, receiving and availing the diverse data. This electronic data provides the foundation of real time data. All this transmission of data needs to be secured. Security is essential for healthcare systems as the present one where the blood pressure recordings provided by the smart bracelet are sent to the user's mobile phone via Bluetooth. The bracelet monitors the pregnant women, but also other users who wish to have their blood pressure under control. The system's server analyses the recordings and announces the user, as well as the associated persons to the user in case of an emergency. The doctors, the medical staff, user and user's family and caregivers have access to the health recordings belonging to the monitored user. Security is a main feature of the electronic healthcare system based on the smart bracelet.
... extensive exclusion criteria. [22][23][24][25][26] Traditional RCTs' use of rigid protocol-based follow-up, with routine assessment of treatment adherence, in a limited patient population also raises questions about their generalizability to routine clinical practice. The enormous expense of traditional RCTs also limits follow-up duration and sample size, reducing their ability to detect rare adverse events. ...
Article
Real-world data (RWD) has been defined as data generated outside of traditional randomized clinical trials (RCTs). Though RWD has received increasing attention from regulatory authorities and professional societies, dividing evidence into that derived from ‘real-world’ vs. ‘non-real-world’ sources provides only one element of a much larger framework for evidence evaluation. Evidence should be evaluated on the source of the data, the method of treatment allocation (whether any intervention being evaluated was assigned or simply observed as used in practice) and the context in which the evidence was generated (overall study design). Under this framework, RWD refers only to data source, and a study incorporates RWD when it primarily uses data collected for non-research purposes, such as insurance claims data or the electronic health record, regardless of study design. Separation of study design, data source, and context enables parallel evaluation of two critical elements: (i) whether a study can support claims of causal inference, which can be assured with a high degree of confidence only in studies where patients are assigned treatments by protocol; and (ii) whether the study population and clinical context mirror clinical practice, a strength of observational studies using data from clinical practice or administrative claims. In this review, we describe the strengths and weaknesses of observational and non-observational studies, and studies involving RWD and non-RWD, through the lens of anticoagulation for atrial fibrillation (AF). Observational studies employing RWD are useful for describing how oral anticoagulants are used in clinical practice, but generally cannot be used to make claims regarding comparative treatment effects. Questions regarding treatment effect generally are best answered through an RCT, and additional pragmatic RCTs are needed to compare different antithrombotic agents for the prevention of thrombotic events in AF. Open in new tabDownload slide
... These rapidly rising drug development costs are driven in part by the same accelerating regulatory complexity that delays drug approval. For example, from 1999 to 2005, unique investigational study procedures grew by 6.5% each year, procedural frequency rose by 8.7% annually, and the number of eligibility criteria per protocol tripled [82]. Additionally, in phase I trials conducted between 2004 and 2007, an average of 45 safety monitoring processes/events were mandated in the first four weeks of the trial [83], while between 2009 and 2012, this had risen to a mean of 105 processes/events [84]. ...
Article
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It takes on average 6–12 years to develop new anticancer drugs from discovery to approval. Effective new agents prolong survival. To demonstrate the importance of rapid drug approval, we calculated life‐years potentially saved if selected agents were approved more rapidly. As illustrative examples, we used 27 trials documenting improvements in survival. We multiplied improvement in median survival by numbers of patients dying annually and multiplied this by number of years from drug discovery until approval. For every year by which time to drug approval could have been shortened, there would have been a median number of life‐years potentially saved of 79,920 worldwide per drug. Median number of life‐years lost between time of drug discovery and approval was 1,020,900 per example. If we were able to use available opportunities to decrease the time required to take a drug from discovery to approval to 5 years, the median number of life‐years saved per example would have been 523,890 worldwide. Various publications have identified opportunities to speed drug development without sacrificing patient safety. While many investigational drugs prove to be ineffective, some significantly prolong survival and/or reduce suffering. These illustrative examples suggest that a substantial number of life‐years could potentially be saved by increasing the efficiency of development of new drugs for advanced malignancies. It takes an average of about 12 years to take an effective new anticancer agent from discovery to full approval and availability to patients, although recently the use of “breakthrough drug” designation has shortened this substantially for some agents. There are several feasible and pragmatic steps that could be taken to shorten this further. We have used examples of some agents that have been approved between 2000 and 2015 to illustrate how shortening the time to drug approval could potentially result in the saving of a very substantial number of life‐years.
... A significant increase in the investigator site burden has been related to the number of unique study procedures and the rise in the average number of inclusion criteria, leading to an impact over the site performance. 43 A very comprehensive study has demonstrated the need of expanding definitions on the scientific misconduct practices beyond fabrication, falsification, and plagiarism and another one has offered a very modest but useful recommendation for fraud prevention (Table 2). 44,45 ...
Article
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p class="abstract"> For many years, the quality concept in clinical trials has been discussed and recommended by Good Clinical Practice (GCP) guidelines. Regulatory Authorities and also the Public Involvement anticipate that the pharmaceutical industry will concentrate on creating quality frameworks amid the arranging and leading of conventions of controlled protocols. Nevertheless, many factors have been suggested as contributing to the occurrence of scientific misconduct within the research field, such as: personal and financial interests, site monitoring, available resources, workload, competition among investigators, and the implicit consent of sponsors. The negligence on data fraud represents not only omission but misconduct as well, in this case, a passive attitude intrinsically related to the act of transgression. A properly culture of research must be based on a fundamental ethos of integrity, openness and honest work of high quality in all parts of the research process. There is a need to change the focus from inspection-based quality improvement to planned systematic quality management within clinical trials. In search for a monitoring improvement, a full statistical way to deal with information recognition comprises of executing however many measurable tests as could be allowed on whatever number clinical information factors as could be expected under varied circumstances. Adoption of specific and preventive clinical trial monitoring procedures can identify potential misconduct and data fraud leading to improvement in overall data quality and scientific reports . </p
... Data management in clinical trials is resource-intensive because many case report forms (CRFs) need to be collected: on average, about 180 pages per patient [1]. This article refers to a CRF as an individual documentation form; therefore, each trial applies a set of CRFs. ...
Article
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Background Clinical trials use many case report forms (CRFs) per patient. Because of the astronomical number of potential CRFs, data element re-use at the design stage is attractive to foster compatibility of data from different trials. The objective of this work is to assess the technical feasibility of a CRF editor with connection to a public metadata registry (MDR) to support data element re-use. ResultsBased on the Medical Data Models portal, an ISO/IEC 11179-compliant MDR was implemented and connected to a web-based CRF editor. Three use cases were implemented: re-use at the form, item group and data element levels. ConclusionsCRF design with data element re-use from a public MDR is feasible. A prototypic system is available. The main limitation of the system is the amount of available MDR content.
... Integration of patient datae.g., non-genomic diagnosticsfrom multiple clinical sites is a non-trivial problem. Traditional clinical trials collect a large amount of data items [3] on average 180 pages per patient. Observational studies apply case report forms (CRFs) or re-use routine care data to collect patient data from multiple sites. ...
Article
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Background The volume and complexity of patient data – especially in personalised medicine – is steadily increasing, both regarding clinical data and genomic profiles: Typically more than 1,000 items (e.g., laboratory values, vital signs, diagnostic tests etc.) are collected per patient in clinical trials. In oncology hundreds of mutations can potentially be detected for each patient by genomic profiling. Therefore data integration from multiple sources constitutes a key challenge for medical research and healthcare. Methods Semantic annotation of data elements can facilitate to identify matching data elements in different sources and thereby supports data integration. Millions of different annotations are required due to the semantic richness of patient data. These annotations should be uniform, i.e., two matching data elements shall contain the same annotations. However, large terminologies like SNOMED CT or UMLS don’t provide uniform coding. It is proposed to develop semantic annotations of medical data elements based on a large-scale public metadata repository. To achieve uniform codes, semantic annotations shall be re-used if a matching data element is available in the metadata repository. Results A web-based tool called ODMedit (https://odmeditor.uni-muenster.de/) was developed to create data models with uniform semantic annotations. It contains ~800,000 terms with semantic annotations which were derived from ~5,800 models from the portal of medical data models (MDM). The tool was successfully applied to manually annotate 22 forms with 292 data items from CDISC and to update 1,495 data models of the MDM portal. Conclusion Uniform manual semantic annotation of data models is feasible in principle, but requires a large-scale collaborative effort due to the semantic richness of patient data. A web-based tool for these annotations is available, which is linked to a public metadata repository.
... The subset of medically useful data models is certainly much smaller, but still very large: In the field of medical research, approximately 200 000 clinical studies are registered (3). The average amount of case report forms (CRFs) per patient in a clinical trial increased from 55 to 180 pages in recent years (4). Therefore >10 million different CRFs were used in these clinical studies. ...
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Introduction: Information systems are a key success factor for medical research and healthcare. Currently, most of these systems apply heterogeneous and proprietary data models, which impede data exchange and integrated data analysis for scientific purposes. Due to the complexity of medical terminology, the overall number of medical data models is very high. At present, the vast majority of these models are not available to the scientific community. The objective of the Portal of Medical Data Models (MDM, https://medical-data-models.org) is to foster sharing of medical data models. Methods: MDM is a registered European information infrastructure. It provides a multilingual platform for exchange and discussion of data models in medicine, both for medical research and healthcare. The system is developed in collaboration with the University Library of Münster to ensure sustainability. A web front-end enables users to search, view, download and discuss data models. Eleven different export formats are available (ODM, PDF, CDA, CSV, MACRO-XML, REDCap, SQL, SPSS, ADL, R, XLSX). MDM contents were analysed with descriptive statistics. Results: MDM contains 4387 current versions of data models (in total 10 963 versions). 2475 of these models belong to oncology trials. The most common keyword (n = 3826) is ‘Clinical Trial’; most frequent diseases are breast cancer, leukemia, lung and colorectal neoplasms. Most common languages of data elements are English (n = 328 557) and German (n = 68 738). Semantic annotations (UMLS codes) are available for 108 412 data items, 2453 item groups and 35 361 code list items. Overall 335 087 UMLS codes are assigned with 21 847 unique codes. Few UMLS codes are used several thousand times, but there is a long tail of rarely used codes in the frequency distribution. Discussion: Expected benefits of the MDM portal are improved and accelerated design of medical data models by sharing best practice, more standardised data models with semantic annotation and better information exchange between information systems, in particular Electronic Data Capture (EDC) and Electronic Health Records (EHR) systems. Contents of the MDM portal need to be further expanded to reach broad coverage of all relevant medical domains. Database URL: https://medical-data-models.org
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Currently, most of the documentation forms that lie behind clinical trials and electronic health records are not accessible to the public. The next step towards sharing data from clinical trials1 is for these forms to be made freely available, and then rationalised. As these are blank forms, issues of data protection don’t arise. There are on …
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