Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial.

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants.

Scientific, ethical, and legal considerations for the inclusion of pregnant people in clinical trials.

Clinical trials to address the COVID-19 public health emergency have broadly excluded pregnant people from participation, illustrating a long-standing trend of clinical trial exclusion that has led to a clear knowledge gap and unmet need in the treatment and prevention of medical conditions experienced during pregnancy and of pregnancy-related conditions. Drugs (includes products such as drugs, biologics, biosimilars and vaccines) approved for a certain medical condition in adults are also approved for use in pregnant adults with the same medical condition, unless contraindicated for use in pregnancy. However, there are limited pregnancy-specific data on risks and benefits of drugs in pregnant people, despite their approval for all adults. The United States Food and Drug Administration-approved medical products are used widely by pregnant people, 90% of whom take at least 1 medication during the course of their pregnancy despite there being sparse data from clinical trials on these products in pregnancy. This overall lack of clinical data precludes informed decision-making, causing clinicians and pregnant patients to have to decide whether to pursue treatment without an adequate understanding of potential effects. Although some United States Food and Drug Administration initiatives and other federal efforts have helped to promote the inclusion of pregnant people in clinical research, broader collaboration and reforms are needed to address challenges related to the design and conduct of trials that enroll pregnant people, and to forge a culture of widespread inclusion of pregnant people in clinical research. This article summarizes the scientific, ethical, and legal considerations governing research conducted during pregnancy, as discussed during a recent subject matter expert convening held by the Duke-Margolis Center for Health Policy and the United States Food and Drug Administration on this topic. This article also recommends strategies for overcoming impediments to inclusion and trial conduct.

Assessing the potential for prevention or earlier detection of on-site monitoring findings from randomised controlled trials: Further analyses of findings from the prospective TEMPER triggered monitoring study.

BACKGROUND/AIMS: Clinical trials should be designed and managed to minimise important errors with potential to compromise patient safety or data integrity, employ monitoring practices that detect and correct important errors quickly, and take robust action to prevent repetition. Regulators highlight the use of risk-based monitoring, making greater use of centralised monitoring and reducing reliance on centre visits. The TEMPER study was a prospective evaluation of triggered monitoring (a risk-based monitoring method), whereby centres are prioritised for visits based on central monitoring results. Conducted in three UK-based randomised cancer treatment trials of investigational medicine products with time-to-event outcomes, it found high levels of serious findings at triggered centre visits but also at visits to matched control centres that, based on central monitoring, were not of concern. Here, we report a detailed review of the serious findings from TEMPER centre visits. We sought to identify feasible, centralised processes which might detect or prevent these findings without a centre visit. METHODS: The primary outcome of this study was the proportion of all 'major' and 'critical' TEMPER centre visit findings theoretically detectable or preventable through a feasible, centralised process. To devise processes, we considered a representative example of each finding type through an internal consensus exercise. This involved (a) agreeing the potential, by some described process, for each finding type to be centrally detected or prevented and (b) agreeing a proposed feasibility score for each proposed process. To further assess feasibility, we ran a consultation exercise, whereby the proposed processes were reviewed and rated for feasibility by invited external trialists. RESULTS: In TEMPER, 312 major or critical findings were identified at 94 visits. These findings comprised 120 distinct issues, for which we proposed 56 different centralised processes. Following independent review of the feasibility of the proposed processes by 87 consultation respondents across eight different trial stakeholder groups, we conclude that 306/312 (98%) findings could theoretically be prevented or identified centrally. Of the processes deemed feasible, those relating to informed consent could have the most impact. Of processes not currently deemed feasible, those involving use of electronic health records are among those with the largest potential benefit. CONCLUSIONS: This work presents a best-case scenario, where a large majority of monitoring findings were deemed theoretically preventable or detectable by central processes. Caveats include the cost of applying all necessary methods, and the resource implications of enhanced central monitoring for both centre and trials unit staff. Our results will inform future monitoring plans and emphasise the importance of continued critical review of monitoring processes and outcomes to ensure they remain appropriate.

Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference.

Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled "Challenges in the Conduct of Clinical Trials in Nephrology" to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.

Risk-adapted monitoring is not inferior to extensive on-site monitoring: Results of the ADAMON cluster-randomised study.

Background According to Good Clinical Practice, clinical trials must protect rights and safety of patients and make sure that the trial results are valid and interpretable. Monitoring on-site has an important role in achieving these objectives; it controls trial conduct at trial sites and informs the sponsor on systematic problems. In the past, extensive on-site monitoring with a particular focus on formal source data verification often lost sight of systematic problems in study procedures that endanger Good Clinical Practice objectives. ADAMON is a prospective, stratified, cluster-randomised, controlled study comparing extensive on-site monitoring with risk-adapted monitoring according to a previously published approach. Methods In all, 213 sites from 11 academic trials were cluster-randomised between extensive on-site monitoring (104) and risk-adapted monitoring (109). Independent post-trial audits using structured manuals were performed to determine the frequency of major Good Clinical Practice findings at the patient level. The primary outcome measure is the proportion of audited patients with at least one major audit finding. Analysis relies on logistic regression incorporating trial and monitoring arm as fixed effects and site as random effect. The hypothesis was that risk-adapted monitoring is non-inferior to extensive on-site monitoring with a non-inferiority margin of 0.60 (logit scale). Results Average number of monitoring visits and time spent on-site was 2.1 and 2.7 times higher in extensive on-site monitoring than in risk-adapted monitoring, respectively. A total of 156 (extensive on-site monitoring: 76; risk-adapted monitoring: 80) sites were audited. In 996 of 1618 audited patients, a total of 2456 major audit findings were documented. Depending on the trial, findings were identified in 18%-99% of the audited patients, with no marked monitoring effect in any of the trials. The estimated monitoring effect is -0.04 on the logit scale with two-sided 95% confidence interval (-0.40; 0.33), demonstrating that risk-adapted monitoring is non-inferior to extensive on-site monitoring. At most, extensive on-site monitoring could reduce the frequency of major Good Clinical Practice findings by 8.2% compared with risk-adapted monitoring. Conclusion Compared with risk-adapted monitoring, the potential benefit of extensive on-site monitoring is small relative to overall finding rates, although risk-adapted monitoring requires less than 50% of extensive on-site monitoring resources. Clusters of findings within trials suggest that complicated, overly specific or not properly justified protocol requirements contributed to the overall frequency of findings. Risk-adapted monitoring in only a sample of patients appears sufficient to identify systematic problems in the conduct of clinical trials. Risk-adapted monitoring has a part to play in quality control. However, no monitoring strategy can remedy defects in quality of design. Monitoring should be embedded in a comprehensive quality management approach covering the entire trial lifecycle.

The potential exploitation of research participants in high income countries who lack access to health care.

There are millions of individuals living in North America and the European Union who lack access to healthcare services. When these individuals participate in research, they are at increased risk of being exposed to the risks and burdens of clinical trials without realizing the benefits that result from them. The mechanisms that have been proposed to ensure that research participants in low- and middle-income countries are not exploited are unlikely to protect participants in high-income countries. The present manuscript argues that one way to address concerns about exploitation in high-income countries would be to require sponsors to provide targeted benefits such as medical treatment during the trial, or the study drug after the trial. The latter could be achieved through extension studies, expanded access programs, or named-patient programs. Sponsors also might provide non-medical benefits, such as education or social support. Ethical and regulatory guidance should be revised to ensure that research participants in high-income countries who lack access to healthcare services receive sufficient benefits.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

What Is Ailing Oncology Clinical Trials? Can We Fix Them?

Evidence from phase three clinical trials helps shape clinical practice. However, a very small minority of patients with cancer participate in clinical trials and many trials are not completed on time due to slow accrual. Issues with restrictive eligibility criteria can severely limit the patients who can access trials, without any convincing evidence that these restrictions impact patient safety. Similarly, regulatory, organizational, and institutional hurdles can delay trial activation, ultimately making some studies irrelevant. Additional issues during trial conduct (e.g., mandatory in-person visits, central confirmation of standard biomarkers, and inflexible drug dosage modification) contribute to making trials non-patient-centric. These real-life observations from experienced clinical trialists can seem nonsensical to investigators and patients alike, who are trying to bring effective drugs to patients with cancer. In this review, we delve into these issues in detail, and discuss potential solutions to make clinical trials more accessible to patients.

Improving completion rates of patient-reported outcome measures in cancer clinical trials: Scoping review investigating the implications for trial designs.

BACKGROUND: Patient-reported outcomes (PROs) play a crucial role in cancer clinical trials. Despite the availability of validated PRO measures (PROMs), challenges related to low completion rates and missing data remain, potentially affecting the trial results' validity. This review explored strategies to improve and maintain high PROM completion rates in cancer clinical trials. METHODOLOGY: A scoping review was performed across Medline, Embase and Scopus and regulatory guidelines. Key recommendations were synthesized into categories such as stakeholder involvement, study design, PRO assessment, mode of assessment, participant support, and monitoring. RESULTS: The review identified 114 recommendations from 18 papers (16 peer-reviewed articles and 2 policy documents). The recommendations included integrating comprehensive PRO information into the study protocol, enhancing patient involvement during the protocol development phase and in education, and collecting relevant PRO data at clinically meaningful time points. Electronic data collection, effective monitoring systems, and sufficient time, capacity, workforce and financial resources were highlighted. DISCUSSION: Further research needs to evaluate the effectiveness of these strategies in various context and to tailor these recommendations into practical and effective strategies. This will enhance PRO completion rates and patient-centred care. However, obstacles such as patient burden, low health literacy, and conflicting recommendations may present challenges in application.

The SHOW RESPECT adaptable framework of considerations for planning how to share trial results with participants, based on qualitative findings from trial participants and site staff.

BACKGROUND: Sharing trial results with participants is a moral imperative, but too often does not happen in appropriate ways. METHODS: We carried out semi-structured interviews with patients (n = 13) and site staff (n = 11), and surveyed 180 patients and 68 site staff who were part of the Show RESPECT study, which tested approaches to sharing results with participants in the context of the ICON8 ovarian cancer trial (ISRCTN10356387). Qualitative and free-text data were analysed thematically, and findings used to develop the SHOW RESPECT adaptable framework of considerations for planning how to share trial results with participants. This paper presents the framework, with illustrations drawn from the Show RESPECT study. RESULTS: Our adaptable 'SHOW RESPECT' framework covers (1) Supporting and preparing trial participants to receive results, (2) HOw will the results reach participants?, (3) Who are the trial participants?, (4) REsults-what do they show?, (5) Special considerations, (6) Provider-who will share results with participants?, (7) Expertise and resources, (8) Communication tools and (9) Timing of sharing results. While the data upon which the framework is based come from a single trial, many of our findings are corroborated by findings from other studies in this area, supporting the transferability of our framework to trials beyond the UK ovarian cancer setting in which our work took place. CONCLUSIONS: This adaptable 'SHOW RESPECT' framework can guide researchers as they plan how to share aggregate trial results with participants. While our data are drawn from a single trial context, the findings from Show RESPECT illustrate how approaches to communication in a specific trial can influence patient and staff experiences of feedback of trial results. The framework generated from these findings can be adapted to fit different trial contexts and used by other researchers to plan the sharing of results with their own participants. TRIAL REGISTRATION: ISRCTN96189403. Registered on February 26, 2019. Show RESPECT was supported by the Medical Research Council (MC_UU_12023/24 and MC_UU_00004/08) and the NIHR CRN.

The ethics of clinical research in the era of COVID-19.

There is an urgent need for increased understanding of COVID-19 and strategies for its prevention, treatment, and mitigation. All participants in the research enterprise, including institutional review boards, have an ethical duty to protect participants and ensure that the benefits gained from such research do not conflict with the core principles that guided researchers prior to the pandemic. In this review, we discuss the ethical issues surrounding initiation and conduct of clinical trials, focusing on novel COVID-19 therapeutic, vaccine, or biospecimen research, using the principles of autonomy, beneficence, and justice. We discuss strategies to manage the practical challenges associated with the conduct of clinical trials, with an emphasis on maintaining the rights and welfare of research participants.

Bringing Patient and Caregivers Voices to the Clinical Trial Chorus: A Report From the BMT CTN Patient and Caregiver Advocacy Task Force.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute for more than 2 decades, is focused on improving the outcomes of hematopoietic cell transplantation (HCT) and other cellular therapies. It answered critical questions about conditioning intensity, donor choice, graft-versus-host disease prevention and treatment, and relapse mitigation strategies in a manner made possible by an extensive network of centers that have enrolled more than 16,000 patients to more than 55 trials. Although the BMT CTN has engaged patients in a variety of ways since its establishment, there is a growing realization that increasing that engagement and including caregivers offers many additional benefits to patients and investigators alike. Bringing the voice of patients and caregivers to clinical trial design is likely to enhance trial participation and reduce barriers to recruitment/retention. Unless clinical trials are designed with unique considerations of patients who have socioeconomic and access challenges, these populations will remain under-represented in HCT trials with limited generalizability of results. The next main frontier in our field is patient and caregiver access to high-quality HCT facilities coupled with the opportunity to participate in relevant, meaningful clinical research. In 2021, the BMT CTN Executive Committee convened a Patient and Caregiver Advocacy Task Force with a diverse membership representing a variety of stakeholders. The charge to the Task Force was to provide achievable recommendations for incorporating patient input at all steps of clinical trial development from initial concept to dissemination of results. Four focus areas were identified: (1) patient and caregiver input in research portfolio; (2) patient engagement in informed consent, protocol development and trial conduct; (3) communication to patients about trial progress, primary outcomes and secondary analyses; and (4) increased awareness among patients who may be considering BMT or cell therapy about BMT CTN trials. Three specific initiatives were considered as high priority by the Task Force: Fostering patient and caregiver engagement in development of the research portfolio and protocols; Developing communication plans for ongoing studies; and Simplifying the process for informed consent to make it more patient friendly. The BMT CTN has established a patient and caregiver advocacy committee that is tasked with developing concrete steps to incorporate recommendations of the BMT CTN Task Force in its current and future work. The BMT CTN recognizes patient and caregivers are valuable partners whose voice will enhance the conduct of impactful trials in BMT and cell therapy.

What is the purpose of clinical trial monitoring?

BACKGROUND: The sources of information on clinical trial monitoring do not give information in an accessible language and do not give detailed guidance. In order to enable communication and to build clinical trial monitoring tools on a strong easily communicated foundation, we identified the need to define monitoring in accessible language. METHODS: In a three-step process, the material from sources that describe clinical trial monitoring were synthesised into principles of monitoring. A poll regarding their applicability was run at a UK national academic clinical trials monitoring meeting. RESULTS: The process derived 5 key principles of monitoring: keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen. CONCLUSION: From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as 5 principles. These principles, given in accessible language, should form a firm basis for discussion of monitoring of clinical trials.

Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units.

BACKGROUND: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. METHODS: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. RESULTS: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. DISCUSSION: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Letter on "Sharing trial results directly with trial participants and other stakeholders after the SARS-CoV-2 pandemic hit the UK - experience from the ActWELL trial".

After the SARS-CoV-2 pandemic took hold in the UK, the ActWELL trial team's plans to present the trial results to participants and other stakeholders had to change. Instead of face-face events, three online events were planned and hosted successfully. In this article, we describe the choices made in planning and organisation of the online events including things we would do differently if we were to do it again. We think that online events are a useful platform when informing participants and other stakeholders of the results of your trial, even beyond the SARS-CoV-2 pandemic, and we hope this article can help other trial teams to plan their own online events.

Making large-scale surgical trials possible: collaboration and the role of surgical trainees.

BACKGROUND: Recruitment to surgical randomised controlled trials (RCTs) can be challenging. The Sunflower study is a large-scale multi-centre RCT that seeks to establish the clinical and cost effectiveness of pre-operative imaging versus expectant management in patients with symptomatic gallstones undergoing laparoscopic cholecystectomy at low or moderate risk of common bile duct stones. Trials such as Sunflower, with a large recruitment target, rely on teamworking. Recruitment can be optimised by embedding a QuinteT Recruitment Intervention (QRI). Additionally, engaging surgical trainees can contribute to successful recruitment, and the NIHR Associate Principal Investigator (API) scheme provides a framework to acknowledge their contributions. METHODS: This was a mixed-methods study that formed a component part of an embedded QRI for the Sunflower RCT. The aim of this study was to understand factors that supported and hindered the participation of surgical trainees in a large-scale RCT and their participation in the API scheme. It comprised semi-structured telephone interviews with consultant surgeons and surgical trainees involved in screening and recruitment of patients, and descriptive analysis of screening and recruitment data. Interviews were analysed thematically to explore the perspectives of-and roles undertaken by-surgical trainees. RESULTS: Interviews were undertaken with 34 clinicians (17 consultant surgeons, 17 surgical trainees) from 22 UK hospital trusts. Surgical trainees contributed to patient screening, approaches and randomisation, with a major contribution to the randomisation of patients from acute admissions. They were often encouraged to participate in the study by their centre principal investigator, and career development was a typical motivating factor for their participation in the study. The study was registered with the API scheme, and a majority of the trainees interviewed (n = 14) were participating in the scheme. CONCLUSION: Surgical trainees can contribute substantial activity to a large-scale multi-centre RCT. Benefits of trainee engagement were identified for trainees themselves, for local sites and for the study as a whole. The API scheme provided a formal framework to acknowledge engagement. Ensuring that training and support for trainees are provided by the trial team is key to optimise success for all stakeholders.

COVID-19 hits a trial: Arguments against hastily deviating from the plan.

The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to supervise trials in the usual way and precautionary measures had to be implemented to care for medication supply and general safety of study participants it is now important to consider, how the impact of the pandemic on trial outcome can be assessed, which measures are needed to decide, how to proceed with the trial and what is needed to compensate to irregularity introduced by the pandemic situation. Obviously not all trials will suffer to the same degree: some trials may be close to finalizing recruitment, others may not yet have started. Similarly not all clinical trials investigate vulnerable patient populations, but some will and may in addition have recruited to an extent that beneficial effects achieved in the initial phase of the trial may be outweighed by an increase e.g. in mortality that impacts both treatment groups. The situation is further complicated by the fact that the pandemic reached different countries in the world and even cities in one country at different points in time with different severity. Our example is a randomized and double-blind clinical trial comparing digitoxin and placebo in patients with advanced chronic heart failure. This trial has recruited roughly 1/3 of the overall 2200 patients when the disease outbreak reached Germany. We discuss how simulations and theoretical considerations can be used to address questions about the need to increase the overall sample-size to be recruited to compensate for a potential shrinkage of the treatment effect caused by the COVID-19 pandemic and what role the degree of consistency could play when comparing pre-, during- and post- COVID-19 periods of trial conduct regarding the question, whether the treatment effect can be considered consistent and with this generalizable. This is dependent on the size of the treatment effect and the impact of the pandemic. We argue, that in case of doubt, it may be wise to proceed with the original study plan.

Open Payments and the US Clinical Landscape.

BACKGROUND: The Open Payments database represents a new, substantial source of information on the US clinical trial investigator landscape. METHODS: This paper draws upon the Open Payments database. This database, mandated by the US Sunshine Act, does help provide a vital missing element in understanding the commercial clinical trial landscape in the United States: comprehensive, detailed, clinical investigator and site information by specific clinical trial. Pharmaceutical companies are required to report all payment detail to US-based physicians, including their participation in US clinical trials. The data are available going back to the second half of 2013 and are updated each year. Data compliance is very high. RESULTS: Open Payments data demonstrate, consistent with ClinicalTrials.gov results, a constancy in the level of commercially sponsored clinical trial activity. The number of active clinical investigators for example has remained unchanged each year since 2013. The percentage of one-time investigators is substantially lower than has often been quoted. A strikingly large percentage of investigators in the United States though participate in a very limited number of clinical trials. A large majority of clinical investigators conduct clinical trials in their private practice. CONCLUSION: Following the US experience, other countries are instituting physician payment databases similar to Open Payments Open Payments provides critical management and operation data, including detailed investigator and site experience data. In addition, it is possible to estimate how investigators performed on each clinical trial.

Monitoring in practice - How are UK academic clinical trials monitored? A survey.

BACKGROUND: Despite the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) encouraging the use of risk-based monitoring for trials in 2013, there remains a lack of evidence-based guidelines on how to monitor. We surveyed the academic United Kingdom Clinical Research Collaboration (UKCRC) registered clinical trials units (CTUs) to find out their policy on monitoring of phase III randomised clinical trials of an investigational medicinal product (CTIMPs). METHODS: An online survey of monitoring policy with sections on the CTU, central monitoring and on-site monitoring was sent to all 50 UKCRC registered CTUs in November 2018. Descriptive data analysis and tabulations are reported using the total number answering each question. RESULTS: A total of 43/50 (86%) of CTUs responded with 38 conducting phase III randomised CTIMP trials. Of these 38 CTUs, 34 finished the survey. Most CTUs (36/37, 97%) use a central monitoring process to guide, target or supplement site visits. More than half (19/36, 53%) of CTUs do not use an automated monitoring report when centrally monitoring trials and all units use trial team knowledge to make a final decision on whether an on-site visit is required. A total of 31/34 (91%) CTUs used triggers to decide whether or not to conduct an on-site monitoring visit. On-site, a mixture of source data verification and checking of processes was carried out. The CTUs overwhelmingly (27/34, 79%) selected optimising central monitoring as their most pressing concern. CONCLUSION: The survey showed a wide variation in phase III randomised CTIMP trial monitoring practices by academic clinical trials units within a single research-active country. We urgently need to develop evidence-based regulator-agreed guidance for CTUs on best practice for both central and on-site monitoring and to develop tools for all CTUs to use.

Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.