Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert "Think Tank" panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

Cost Drivers of a Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Phase 3 Clinical Trial.

Background: Studies indicate that the prevalence of multidrug-resistant infections, including hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), has been rising. There are many challenges associated with these disease conditions and the ability to develop new treatments. Additionally, HABP/VABP clinical trials are very costly to conduct given their complex protocol designs and the difficulty in recruiting and retaining patients. Methods: With input from clinicians, representatives from industry, and the US Food and Drug Administration, we conducted a study to (1) evaluate the drivers of HABP/VABP phase 3 direct and indirect clinical trial costs; (2) to identify opportunities to lower these costs; and (3) to compare (1) and (2) to endocrine and oncology clinical trials. Benchmark data were gathered from proprietary and commercial databases and used to create a model that calculates the fully loaded (direct and indirect) cost of typical phase 3 HABP/VABP endocrine and oncology clinical trials. Results: Results indicate that the cost per patient for a 200-site, 1000-patient phase 3 HABP/VABP study is $89600 per patient. The cost of screen failures and screen failure rates are the main cost drivers. Conclusions: Results indicate that biopharmaceutical companies and regulatory agencies should consider strategies to improve screening and recruitment to decrease HABP/VABP clinical trial costs.

Streamlining Safety Data Collection in Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Trials: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: Resistant bacteria are one of the leading causes of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). HABP/VABP trials are complex and difficult to conduct due to the large number of medical procedures, adverse events, and concomitant medications involved. Differences in the legislative frameworks between different regions of the world may also lead to excessive data collection. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development (ABDD) by streamlining clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with current data collection processes. Experts defined "data collection" as the act of capturing and reporting certain data on the case report form as opposed to recording of data as part of routine clinical care. The ABDD Project Team developed strategies for streamlining safety data collection in HABP/VABP trials using a Quality by Design approach. RESULTS: Current safety data collection processes in HABP/VABP trials often include extraneous information. More targeted strategies for safety data collection in HABP/VABP trials will rely on optimal protocol design and prespecification of which safety data are essential to satisfy regulatory reporting requirements. CONCLUSIONS: A consensus and a cultural change in clinical trial design and conduct, which involve recognition of the need for more efficient data collection, are urgently needed to advance ABDD and to improve HABP/VABP trials in particular.

Enhancing clinical evidence by proactively building quality into clinical trials.

BACKGROUND: Stakeholders across the clinical trial enterprise have expressed concern that the current clinical trial enterprise is unsustainable. The cost and complexity of trials have continued to increase, threatening our ability to generate reliable evidence essential for making appropriate decisions concerning the benefits and harms associated with clinical interventions. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight. METHODS: The Clinical Trials Transformation Initiative convened a project to evaluate methods to prospectively build quality into the scientific and operational design of clinical trials ("quality-by-design"), such that trials are feasible to conduct and important errors are prevented rather than remediated. A working group evaluated aspects of trial design and oversight and developed the Clinical Trials Transformation Initiative quality-by-design principles document, outlining a series of factors generally relevant to the reliability of trial conclusions and to patient safety. These principles were then applied and further refined during a series of hands-on workshops to evaluate their utility in facilitating proactive, cross-functional dialogue, and decision-making about trial design and planning. Following these workshops, independent qualitative interviews were conducted with 19 workshop attendees to explore the potential challenges for implementing a quality-by-design approach to clinical trials. The Clinical Trials Transformation Initiative project team subsequently developed recommendations and an online resource guide to support implementation of this approach. CONCLUSION: The Clinical Trials Transformation Initiative quality-by-design principles provide a framework for assuring that clinical trials adequately safeguard participants and provide reliable information on which to make decisions on the effects of treatments. The quality-by-design workshops highlighted the value of active discussions incorporating the different perspectives within and external to an organization (e.g. clinical investigators, research site staff, and trial participants) in improving trial design. Workshop participants also recognized the value of focusing oversight on those aspects of the trial where errors would have a major impact on participant safety and reliability of results. Applying the Clinical Trials Transformation Initiative quality-by-design recommendations and principles should enable organizations to prioritize the most critical determinants of a trial's quality, identify non-essential activities that can be eliminated to streamline trial conduct and oversight, and formulate appropriate plans to define, avoid, mitigate, monitor, and address important errors.

Participant comprehension and acceptability of enhanced versus text-only electronic informed consent: an innovative qualitative pilot study.

BACKGROUND: The use of electronic informed consent (eIC) in decentralized trials offers a pragmatic approach to enrolling participants across multiple geographic areas. METHODS: Using a randomized, cross-over study design, we conducted a qualitative descriptive evaluation of two eIC approaches-text-only eIC and enhanced eIC-in a mock hypertension Phase III clinical trial. We assessed participant comprehension and acceptability (usability, satisfaction, and eIC preference). RESULTS: A total of 24 individuals with hypertension participated in the study: 12 reviewed the text-only eIC first, followed by the enhanced eIC, and 12 reviewed the enhanced eIC first, followed by the text-only eIC. The study population was diverse in gender, age, race, and geographic location. We found no descriptive differences in participant comprehension and satisfaction between the two eIC approaches. However, more participants preferred the enhanced eIC, and participants indicated that the digital elements were personable and made them feel more informed, engaged, comfortable, and prepared to participate in clinical research. CONCLUSIONS: Our findings suggest that enhancing the eIC process with digital elements may have beneficial outcomes among potential participants beyond comprehension and satisfaction.

A framework for assessing clinical trial site readiness.

Clinical trial processes are unnecessarily inefficient and costly, slowing the translation of medical discoveries into treatments for people living with disease. To reduce redundancies and inefficiencies, a group of clinical trial experts developed a framework for clinical trial site readiness based on existing trial site qualifications from sponsors. The site readiness practices are encompassed within six domains: research team, infrastructure, study management, data collection and management, quality oversight, and ethics and safety. Implementation of this framework for clinical trial sites would reduce inefficiencies in trial conduct and help prepare new sites to enter the clinical trials enterprise, with the potential to improve the reach of clinical trials to underserved communities. Moreover, the framework holds benefits for trial sponsors, contract research organizations, trade associations, trial participants, and the public. For novice sites considering future trials, we provide a framework for site preparation and the engagement of stakeholders. For experienced sites, the framework can be used to assess current practices and inform and engage sponsors, staff, and participants. Details in the supplementary materials provide easy access to key regulatory documents and resources. Invited perspective articles provide greater depth from a systems, DEIA (diversity, equity, inclusion, and accessibility) and decentralized trials perspective.

Assessing the Financial Value of Decentralized Clinical Trials.

BACKGROUND: Deployment of remote and virtual clinical trial methods and technologies, referred to collectively as decentralized clinical trials (DCTs), represents a profound shift in clinical trial practice. To our knowledge, a comprehensive assessment of the financial net benefits of DCTs has not been conducted. METHODS: We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess the financial impact of DCTs. The measure of DCT value is the increment in eNPV that occurs, on average, when DCT methods are employed in comparison to when they are not. The model is populated with parameter values taken from published studies, Tufts CSDD benchmark data, and Medable Inc. data on DCT projects. We also calculated the return on investment (ROI) in DCTs as the ratio of the increment in eNPV to the DCT implementation cost. RESULTS: We found substantial value from employing DCT methods in phase II and phase III trials. If we assume that DCT methods are applied to both phase II and phase III trials the increase in value is $20 million per drug that enters phase II, with a seven-fold ROI. CONCLUSIONS: DCTs can provide substantial extra value to sponsors developing new drugs, with high returns to investment in these technologies. Future research on this topic should focus on expanding the data to larger datasets and on additional aspects of clinical trial operations not currently measured.

Regulatory Acceptance of Patient-Reported Outcome (PRO) Data from Bring-Your-Own-Device (BYOD) Solutions to Support Medical Product Labeling Claims : Let's Share the Success Stories to Move the Industry Forward.

Bring-your-own-device (BYOD) methods for collecting patient-reported outcome (PRO) data in clinical trials can decrease patient burden and improve data quality. However, adoption of BYOD in clinical trials is limited by the absence of publicly available case studies where BYOD PRO data supported regulatory medical product approvals. Anecdotally, we are aware of multiple examples where efficacy and safety label claims were based on BYOD PRO data; however-except for one-these examples have not been made public. The absence of these case studies can lead sponsors to be hesitant to use BYOD for capturing primary and secondary PRO-based endpoints in their trials. This commentary outlines the context of the issue faced and concludes with a call for sponsor transparency with regard to BYOD use through publicizing where approved labeling claims were based on BYOD data. We suggest how this data could be systematically captured going forward. Sharing this information will benefit the clinical trials enterprise by increasing confidence in the utilization of BYOD and provide opportunities to enhance patient-centricity.

Stakeholders' views on the most and least helpful aspects of the ICH E6 GCP guideline and their aspirations for the revision of ICH E6(R2).

Background: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has published the ICH E6(R2) Good Clinical Practice (GCP) guideline, which provides standards for the design, conduct, documentation, and reporting of clinical trials. Revision to E6(R2) is currently underway, aiming to adapt the guidance to the current regulatory environment. The Clinical Trials Transformation Initiative (CTTI) interviewed stakeholders, gathering their experiences implementing ICH E6 GCP and suggestions for revising the guidance. Methods: We conducted a qualitative descriptive study using in-depth interviews. Participants were purposefully selected to ensure diversity in geography, research role, and type of institution. Participants reflected on their aspirations for the ICH E6 GCP revision and described sections of the guidance that they found most and least helpful. Narratives were analyzed using applied thematic analysis. Results: Many participants found ICH E6 GCP generally clear and helpful. They appreciated that the guidance is globally accepted and serves as a common standard for research worldwide. Participants also noted opportunities for improvement, suggesting that the revised guidance should incorporate flexibility, simplify requirements, and accommodate advances in research conduct. They highlighted areas where language should be updated and concepts clarified and expressed a desire for transparency and inclusiveness in the revision process. Conclusion: Our findings show that many participants view the ICH E6(R2) guidance as helpful overall, although substantial room for improvement remains. We have provided the full report of these findings to ICH in hopes that it will be useful as the E6 GCP guideline is revised.

PROPHETIC EU: Prospective Identification of Pneumonia in Hospitalized Patients in the Intensive Care Unit in European and United States Cohorts.

Background: The prospective identification of patients at high risk for hospital-acquired/ventilator-associated bacterial pneumonia may improve clinical trial feasibility and foster antibacterial development. In a prior study conducted in the United States, clinical criteria were used to prospectively identify these patients; however, these criteria have not been applied in a European population. Methods: Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of 7 European hospitals were prospectively enrolled from June 12 to December 27, 2017. We estimated the proportion of high-risk patients developing pneumonia according to US Food and Drug Administration guidance and a subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, treatment exposures, and pneumonia incidence in a European cohort and a previously described US cohort. Results: Of 888 high-risk patients, 211/888 (24%) were treated for possible pneumonia, and 150/888 (17%) met the Food and Drug Administration definition for hospital-acquired/ventilator-associated bacterial pneumonia. A higher proportion of European patients treated for possible pneumonia met the pneumonia definition (150/211 [71%] vs 537/1464 [37%]; P < .001). Among patients developing pneumonia, a higher proportion of European patients met antibacterial trial eligibility criteria (124/150 [83%] vs 371/537 [69%]; P < .001). Conclusions: Clinical criteria prospectively identified high-risk patients with high rates of pneumonia in the European cohort. Despite higher rates of established risk factors and incident pneumonia, European patients were significantly less likely to receive antibiotics for possible pneumonia than US patients. Different treatment practices may contribute to lower rates of antibacterial trial enrollment in the United States.

Stakeholders' recommendations for revising Good Clinical Practice.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is revising ICH E6 Good Clinical Practice (GCP). The Clinical Trials Transformation Initiative (CTTI) initiated a project to identify and provide ICH with stakeholders' priority areas and suggestions for revising ICH E6 GCP. We conducted a global online survey to identify areas of ICH E6 GCP that are and are not in need of revision. A total of 327 stakeholders completed the survey. Stakeholders represent many research roles and types of organizations, are employed in 39 countries, and conduct research in 153 countries. The ICH E6 GCP principles mentioned most often (range, 25%-29%) in need of revision were implementing systems that assure quality, providing medical care by qualified physicians/dentists, protecting confidentiality and privacy, obtaining informed consent, and documenting and storing information. The Investigator section (n = 244, 75%) and Sponsor section (n = 242, 74%) of ICH E6 GCP were identified as needing the most revision and the Investigator Brochure section (n = 166, 51%) as needing the least revision. The topic most frequently mentioned as needing revision is Monitoring (n = 146; 45%) in the Sponsor section. Although none of the principles or topics in ICH E6 GCP were identified as needing revision by the majority of stakeholders, a meaningful percentage of stakeholders identified areas that they believe need revision. These findings, which represent the views of a wide variety of stakeholders, may be useful to ICH for identifying where specifically to focus their revision efforts. CTTI provided the final report to ICH with the project findings for their consideration.

BioMeT and Algorithm Challenges: A Proposed Digital Standardized Evaluation Framework.

Technology is advancing at an extraordinary rate. Continuous flows of novel data are being generated with the potential to revolutionize how we better identify, treat, manage, and prevent disease across therapeutic areas. However, lack of security of confidence in digital health technologies is hampering adoption, particularly for biometric monitoring technologies (BioMeTs) where frontline healthcare professionals are struggling to determine which BioMeTs are fit-for-purpose and in which context. Here, we discuss the challenges to adoption and offer pragmatic guidance regarding BioMeTs, cumulating in a proposed framework to advance their development and deployment in healthcare, health research, and health promotion. Furthermore, the framework proposes a process to establish an audit trail of BioMeTs (hardware and algorithms), to instill trust amongst multidisciplinary users.

PROPHETIC: Prospective Identification of Pneumonia in Hospitalized Patients in the ICU.

BACKGROUND: Pneumonia is the leading infection-related cause of death. The use of simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials. RESEARCH QUESTION: What are the clinical criteria and contemporary epidemiology trends that are helpful in the identification of patients at high risk of nosocomial pneumonia? STUDY DESIGN AND METHODS: Within the ICUs of 28 US hospitals, we conducted a prospective cohort study among adults who had been hospitalized >48 hours and were considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients who experienced the development of nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures that are associated with increased risk of pneumonia development during the ICU admission. RESULTS: Between February 6, 2016, and October 7, 2016, 4,613 high-risk patients were enrolled. Among 1,464 high-risk patients (32%) who were treated for possible nosocomial pneumonia, 537 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures that are associated with increased risk of nosocomial pneumonia development (c-statistic, 0.709; 95% CI, 0.686-0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days. INTERPRETATION: Treatment for nosocomial pneumonia is common among patients in the ICU who are receiving high levels of respiratory support, yet more than one-half of patients who are treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.

Trends in clinical trial investigator workforce and turnover: An analysis of the U.S. FDA 1572 BMIS database.

BACKGROUND: High turnover rates among clinical trial investigators contribute to inefficiency, instability, and increased costs for the clinical research enterprise; however, factors contributing to investigator turnover have not been well characterized. METHODS: Using information from the U.S. Food and Drug Administration's Bioresearch Monitoring Information System (BMIS), we examined trends in the overall clinical investigator workforce and within specific "phenotypes" as well as differences by investigator location (U.S.-based vs. non-U.S.-based). We identified unique investigators within the database, stratifying them into one of three "phenotypes": those with one Form FDA1572 submission across the study interval ("one-and-done"); those with two or more submissions but with substantial intervals between trials ("stop-and-go"); and those with two or more submissions and continuous involvement in multiple trials ("stayers"). RESULTS: Of the 172,453 unique investigators who submitted a Form FDA 1572 during the study interval (1999-2015), 85,455 were classified as "one-and-done" investigators; 21,768 as "stop-and-go" investigators; and 65,231 as "stayer" investigators. The total number of investigators declined across the study interval. Among all subgroups, only "one-and-done" investigators showed growth across the study period, largely driven by increases in non-U.S.-based investigators. "Stop-and-go" investigators showed declines for both U.S.-based and non-U.S.-based investigators, as did "stayers," who showed the largest absolute and proportional declines of all subgroups. CONCLUSIONS: From 1999 to 2015, investigators submitting a Form FDA 1572 to the BMIS database declined by approximately one-third and the proportion of investigators involved in only one trial increased, signaling potential adverse trends in the clinical investigator workforce. Strategies for sustaining investigator engagement warrant further exploration.

Education and training of clinical and translational study investigators and research coordinators: A competency-based approach.

INTRODUCTION: Training for the clinical research workforce does not sufficiently prepare workers for today's scientific complexity; deficiencies may be ameliorated with training. The Enhancing Clinical Research Professionals' Training and Qualifications developed competency standards for principal investigators and clinical research coordinators. METHODS: Clinical and Translational Science Awards representatives refined competency statements. Working groups developed assessments, identified training, and highlighted gaps. RESULTS: Forty-eight competency statements in 8 domains were developed. CONCLUSIONS: Training is primarily investigator focused with few programs for clinical research coordinators. Lack of training is felt in new technologies and data management. There are no standardized assessments of competence.

Enhancing Clinical Research Professionals' Training and Qualifications (ECRPTQ): Recommendations for Good Clinical Practice (GCP) training for investigators and study coordinators.

INTRODUCTION: The translation of discoveries to drugs, devices, and behavioral interventions requires well-prepared study teams. Execution of clinical trials remains suboptimal due to varied quality in design, execution, analysis, and reporting. A critical impediment is inconsistent, or even absent, competency-based training for clinical trial personnel. METHODS: In 2014, the National Center for Advancing Translational Science (NCATS) funded the project, Enhancing Clinical Research Professionals' Training and Qualifications (ECRPTQ), aimed at addressing this deficit. The goal was to ensure all personnel are competent to execute clinical trials. A phased structure was utilized. RESULTS: This paper focuses on training recommendations in Good Clinical Practice (GCP). Leveraging input from all Clinical and Translational Science Award hubs, the following was recommended to NCATS: all investigators and study coordinators executing a clinical trial should understand GCP principles and undergo training every 3 years, with the training method meeting the minimum criteria identified by the International Conference on Harmonisation GCP. CONCLUSIONS: We anticipate that industry sponsors will acknowledge such training, eliminating redundant training requests. We proposed metrics to be tracked that required further study. A separate task force was composed to define recommendations for metrics to be reported to NCATS.

The Clinical Trials Transformation Initiative: innovation through collaboration.

The Clinical Trials Transformation Initiative (CTTI) identifies and promotes practices to increase the quality and efficiency of clinical trials through projects that generate empirical data on how trials are currently conducted, leading to recommendations for improvement.