Trial Protocol Development Research Articles

Managing protocol development with international teams: Soft skill perspectives from a global team of protocol writers

Clinical trial protocol development forms part of the critical path for launching a trial, which means timelines are tight and progress must be fast and sustained throughout the protocol’s development. In order to be successful, medical writers require well-developed soft skills to meet the needs of the trial team and to produce a high-quality protocol. We focus on five critical soft skills that are essential for medical writers working with international teams: critical thinking, leadership, communication, teamwork, and adaptability. Based on our experience as a global team of protocol subject matter experts from Asia-Pacific, Europe, India, South Africa, and the US, we also discuss soft skills that are important for working with team members across different regions.

How To Prepare a Protocol

Nowadays it is necessary to facilitate clinical trial development. It seems difficult to assure the appropriate items to outline a protocol for a clinical trial appropriately. Therefore, clarity helps to rise comprehensive clinical trial protocol development structures. Conciseness and clarity are necessary to facilitate the process of clinical trial protocol preparation. The article aims to guide the reader to fulfil correctly all the requirements for the best protocol lending. Template applies easily to the aim of this facility. Nevertheless, the article “How to Prepare a Protocol for a Clinical Trial? 5 Step Advice” sketches clearly five steps to ensure the quality to your protocol outlines. Administrative information, inclusion/exclusion criteria, ethic principles, general governance and data management are basic for a successful protocol approval. No doubt the process of preparation needs a careful filling The appropriate elements can satisfy the requirements for a careful drafting. The article outlines a guide for readers on the appropriate skills. Thus, the article makes possible to get forward on the preparation process promptly. In conclusion the article is a guide can satisfy your basic question on protocol trail structuring.

Patient and public involvement to inform the protocol of a clinical trial comparing total hip arthroplasty with exercise: an exploratory qualitative case study

ObjectiveTo explore patient, clinician and decision-maker perceptions on a clinical trial evaluating the effectiveness of total hip arthroplasty (THA) compared with exercise to inform the trial protocol.DesignThis is an exploratory...

Evaluation of cultural competency in a South African cluster randomised controlled trial: lessons learned for trial reporting standards

BackgroundFailure to consider relevant cultural, ethnic and diversity parameters (and the intersection between these parameters) during trial protocol development and trial conduct may negatively impact recruitment, intervention development and delivery, and participant adherence and retention, potentially reducing overall internal validity. This case study aimed to evaluate the utility and comparability between the 9-item Gibbs Framework to measure cultural competency and the GRIPP-2(Short Form (SF)) 5-point checklist to assess patient and public involvement in the context of a complex clinical trial conducted in an African setting.MethodsWe identified and collated all relevant publications, source and procedural data related to the trial and integrated the documents into a dynamic trial timeline. Two independent investigators applied and scored the Gibbs Framework and the GRIPP-2(SF) checklist to the four publications arising from the trial, noting functionality and comparability between tools. Where cultural competency was not met, a third investigator screened all procedural and source data and identified if cultural competency had been achieved but not reported in the publications, or if the trial had not met appropriate cultural competency based on the documentation.ResultsApplication of the Gibbs Framework found that the trial scored ‘2’ for seven of the nine Gibbs items, indicating full cultural competency for those questions. The Framework indicated that the trial research question was not driven by the articulated needs of patients, and neither were patients, caregivers and clinical providers involved in the development of the intervention. Comparability with the GRIPP-2(SF) checklist showed that the Gibbs performed better on evaluation of partnerships with the community, identification of culturally competent data sources and target populations, and appointment of trial staff in an inclusive manner.ConclusionsComprehensive evaluation of the trial’s cultural competency required scrutiny of both published manuscripts and source and procedural data, suggesting that there is a gap in current trial reporting standards with respect to cultural competence.Trial registrationPACTR201610001825403. Registered on 17 October 2016.

Amputee, clinician, and regulator perspectives on current and prospective upper extremity prosthetic technologies

ABSTRACT Existing prosthetic technologies for people with upper limb amputation are being adopted at moderate rates. Once fitted for these devices, many upper limb amputees report not using them regularly or at all. The primary aim of this study was to solicit feedback about prosthetic technology and important device design criteria from amputees, clinicians, and device regulators. We compare these perspectives to identify common or divergent priorities. Twenty-one adults with upper limb loss, 35 clinicians, and 3 regulators completed a survey on existing prosthetic technologies and a conceptual sensorimotor prosthesis driven by implanted myoelectric electrodes with sensory feedback via spinal root stimulation. The survey included questions from the Trinity Amputation and Prosthesis Experience Scale, the Disabilities of the Arm, Shoulder, and Hand, and novel questions about technology acceptance and neuroprosthetic design. User and clinician ratings of satisfaction with existing devices were similar. Amputees were most accepting of the proposed sensorimotor prosthesis (75.5% vs clinicians (68.8%), regulators (67.8%)). Stakeholders valued user-centered outcomes like individualized task goals, improved quality of life, device reliability, and user safety; regulators emphasized these last two. The results of this study provide insight into amputee, clinician, and regulator priorities to inform future upper-limb prosthetic design and clinical trial protocol development.

A Study of Regulatory Challenges of Pediatric Oncology Phase I/II Trial Submissions and Guidance on Protocol Development.

The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. "Toxicity and safety" was the most prominent category (27.6%), followed by "Manufacturing and Import" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient-facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time-consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided.

A Call for Pediatric COVID-19 Clinical Trials.

* Abbreviations: COVID-19 — : coronavirus disease 2019 CQ — : chloroquine HCQ — : hydroxychloroquine SARS-CoV-2 — : severe acute respiratory syndrome coronavirus 2 Should children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection receive antiviral therapy? If so, what should we give, to which children, and for what disease severity? Despite brisk scientific progress elucidating the biology and transmission of SARS-CoV-2, and numerous adult trials testing antiviral therapies, we may pass the formative stages of this pandemic without defining antiviral agents’ appropriate role in pediatric management. We urgently need pediatric clinical trials to establish the efficacy, safety, and pharmacokinetics of the most promising experimental and repurposed coronavirus disease 2019 (COVID-19) therapies proposed to date.1 Researchers of early reports show that pediatric SARS-CoV-2 infection tends to be mild but that some children develop severe disease.2 In these reports, researchers highlight differences between pediatric and adult COVID-19 and argue that risk/benefit calculations of therapies derived from adult trials cannot be readily extrapolated to children. Gaps in our knowledge of pediatric COVID-19 further complicate assessments of risk and benefit. To date, we have a limited understanding of viral kinetics or immune responses in children, what factors predispose some children to severe disease, or how these variables affect responses to therapies. We have equally limited comprehension of how SARS-CoV-2 affects children with primary immunodeficiencies, illnesses requiring immune-compromising therapies, or other complex conditions. Nonetheless, treatment planning for severe pediatric cases, even if they will be few, has spurred children’s hospitals to develop algorithms that include antiviral agents, such as remdesivir, chloroquine (CQ), and … Address correspondence to Jeffrey I. Campbell, MD, Division of Infectious Diseases, Boston Children’s Hospital, 333 Longwood Ave, 6th Floor, Boston, MA 02115. E-mail: jeffrey.campbell{at}childrens.harvard.edu

Risk of contamination when planning psychological therapy trials can be assessed using a simple framework

ObjectivesThe objective of this study was to develop and pilot a standard framework that could be used to assess risk of contamination in psychological therapy trials, at the protocol development stage. Study Design and SettingWe developed and piloted a risk of contamination framework on a sample of 100 psychological therapy trial protocols registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry (www.isrctn.com). We assessed all protocols as being low or high risk via three possible sources of contamination: 1) participants in the control arm, 2) participants in the intervention arm, 3) therapists in the intervention arm. ResultsOverall, we found that the risk of contamination across all three sources was low for most studies (86 of 100 trial protocols; 86%). We identified 14 studies that had a potentially high risk for contamination. Most of these (N = 10) were identified as risk of contamination arising from a therapist in the intervention arm. ConclusionThe risk of contamination framework we piloted in this study could be a helpful tool for researchers aiming to identify and manage risk of contamination in their trial protocol development. We found that the risk of contamination was relatively low in the psychological therapy trials we sampled for this study, as measured by our framework, and could usually be mitigated through reasonable adjustments to the study design.

EP.88Development of clinical trial simulation tool for Duchenne muscular dystrophy through the Duchenne Regulatory Science Consortium

Developing clinical trial protocols that give definitive answers as to whether potential new therapies are effective for rare diseases is challenging due to the small population sizes, limitations on availability of natural history data and limited understanding of disease progression. In Duchenne muscular dystrophy (DMD) this has contributed to few trials meeting primary endpoints, and led to questions as to how best to evaluate efficacy of therapeutic candidates. The Duchenne Regulatory Science Consortium (D-RSC) is a public-private-partnership that aims to develop quantitative tools to accelerate drug development and seeks approval of such tools through regulatory pathways at FDA (Food and Drug Administration) and EMA (European Medicines Authority) to confirm utility and value. D-RSC is developing a multivariate model-based clinical trial simulation (CTS) tool, based on longitudinal models of endpoints that span the course of disease (velocity of completion of supine to stand test, 4-stair climb test, and 10-meter walk/run test, NorthStar Ambulatory Assessment, forced vital capacity and Brooke scale). Models include covariates that predict differences in DMD progression such as use of steroids, height, weight, genetics and baseline function. D-RSC has integrated data from 14 independent studies using CDISC standards, the largest DMD clinical database currently available. The final analysis data set after exclusions, excluding missing observations, includes 1139 individuals with a total of 24210 observations of the endpoints from 4 to 34 years of age. The CTS tool that will be developed based on the disease progression models will help drug developers determine optimal clinical study characteristics, including selection of endpoints, inclusion criteria, trial design, size and duration. This will allow development of trial protocols using the lowest number of patients and in the least time possible to reach conclusive decisions on drug efficacy.

Recruitment & retention program for the NeuroNEXT SMA Biomarker Study: Super Babies for SMA!

Background/AimsRecruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible.MethodsIn 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study.ResultsAll healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll.ConclusionsA proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

Development of New Trial Protocol Development Process Chart using Quality by Design method

Development of New Trial Protocol Development Process Chart using Quality by Design method

Impact of Eligibility Criteria on Participant Enrollment for a Randomized Clinical Trial of Gonorrhea Treatment.

High rates of failure to qualify for clinical trial participation increase time and cost required for study completion. Identification of remediable reasons for prescreen failure can help reduce prescreen failure rates and improve study cost effectiveness. Reasons for prescreen failure to qualify for participation in a phase 2 randomized clinical trial of treatment of uncomplicated urogenital gonorrhea were collected from prescreening logs. Reasons were categorized based on whether the reason was that the subject failed to meet eligibility criteria or declined participation. Subjects who failed prescreening but could have been enrolled under protocol amendments were used to estimate potential cost savings had enrollment completed sooner. Over 88% (1373/1554) of potential study candidates were not enrolled. The majority (68.8%) of nonenrolled subjects failed prescreening due to not meeting eligibility criteria, whereas 31.0% declined to participate. The most common reasons for failure to qualify were having only nonurogenital gonorrhea (16.4%), limited time (13.1%), and being on antiretroviral therapy (7.5%). Potential cost savings if protocol amendments affecting eligibility had been instituted earlier were estimated at US $127,500. Careful attention to reasons for prescreen failure can inform clinical trial protocol development to address trial design features that may impact successful enrollment. More efficient subject enrollment can result in substantial cost savings.

Duchenne Regulatory Science Consortium Meeting on Disease Progression Modeling for Duchenne Muscular Dystrophy.

Introduction: The Duchenne Regulatory Science Consortium (D-RSC) was established to develop tools to accelerate drug development for DMD. The resulting tools are anticipated to meet validity requirements outlined by qualification/endorsement pathways at both the U.S. Food and Drug Administration (FDA) and European Medicines Administration (EMA), and will be made available to the drug development community. The initial goals of the consortium include the development of a disease progression model, with the goal of creating a model that would be used to forecast changes in clinically meaningful endpoints, which would inform clinical trial protocol development and data analysis. Methods: In April of 2016 the consortium and other experts met to formulate plans for the development of the model. Conclusions: Here we report the results of the meeting, and discussion as to the form of the model that we plan to move forward to develop, after input from the regulatory authorities.

Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment.

The design of phase I studies is often challenging, because of limited evidence to inform study protocols. Adaptive designs are now well established in cancer but much less so in other clinical areas. A phase I study to assess the safety, pharmacokinetic profile and antiretroviral efficacy of C34‐PEG4‐Chol, a novel peptide fusion inhibitor for the treatment of HIV infection, has been set up with Medical Research Council funding. During the study workup, Bayesian adaptive designs based on the continual reassessment method were compared with a more standard rule‐based design, with the aim of choosing a design that would maximise the scientific information gained from the study. The process of specifying and evaluating the design options was time consuming and required the active involvement of all members of the trial's protocol development team. However, the effort was worthwhile as the originally proposed rule‐based design has been replaced by a more efficient Bayesian adaptive design. While the outcome to be modelled, design details and evaluation criteria are trial specific, the principles behind their selection are general. This case study illustrates the steps required to establish a design in a novel context. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd

Conception, Development, and Clinical Trial Design of Point-of-care Technologies: A Case of Improved FES Device Development

Abstract Objective This article presents a case study on the development of an indigenous stimulator device, including the design of its clinical trials and the process of its clinical trial registration in the newly launched clinical trial registry- India (CTRI). The ethical and regulatory issues involved in medical device clinical trials in India are also discussed. Design and Methods The entire development and trial cycle of a new medical device from ideation to technology transfer is explained in this case of a newly developed indigenous FES device. The primary emphasis is on how to systematically analyse the global trial registry databases to adequately frame a medical device trial. With this case study, we present how to shortlist relevant trials; we then compare them and explain the valid methods for registering a trial protocol in the CTRI. Conclusions Our work can act as a model or guide for rehabilitation researchers in India, facilitating there work in the medical device design and trial protocol development. Though our trial has been designed for and registered in the Indian CTRI trial registry, our work can be equally useful for researchers abroad who desire to conduct their medical device trials in India.

Patient-reported outcome (PRO) assessment in clinical trials: a systematic review of guidance for trial protocol writers.

BackgroundEvidence suggests there are inconsistencies in patient-reported outcome (PRO) assessment and reporting in clinical trials, which may limit the use of these data to inform patient care. For trials with a PRO endpoint, routine inclusion of key PRO information in the protocol may help improve trial conduct and the reporting and appraisal of PRO results; however, it is currently unclear exactly what PRO-specific information should be included. The aim of this review was to summarize the current PRO-specific guidance for clinical trial protocol developers.Methods and FindingsWe searched the MEDLINE, EMBASE, CINHAL and Cochrane Library databases (inception to February 2013) for PRO-specific guidance regarding trial protocol development. Further guidance documents were identified via Google, Google scholar, requests to members of the UK Clinical Research Collaboration registered clinical trials units and international experts. Two independent investigators undertook title/abstract screening, full text review and data extraction, with a third involved in the event of disagreement. 21,175 citations were screened and 54 met the inclusion criteria. Guidance documents were difficult to access: electronic database searches identified just 8 documents, with the remaining 46 sourced elsewhere (5 from citation tracking, 27 from hand searching, 7 from the grey literature review and 7 from experts). 162 unique PRO-specific protocol recommendations were extracted from included documents. A further 10 PRO recommendations were identified relating to supporting trial documentation. Only 5/162 (3%) recommendations appeared in ≥50% of guidance documents reviewed, indicating a lack of consistency.ConclusionsPRO-specific protocol guidelines were difficult to access, lacked consistency and may be challenging to implement in practice. There is a need to develop easily accessible consensus-driven PRO protocol guidance. Guidance should be aimed at ensuring key PRO information is routinely included in appropriate trial protocols, in order to facilitate rigorous collection/reporting of PRO data, to effectively inform patient care.

Evaluating protocol lifecycle time intervals in HIV/AIDS clinical trials.

Identifying efficacious interventions for the prevention and treatment of human diseases depends on the efficient development and implementation of controlled clinical trials. Essential to reducing the time and burden of completing the clinical trial lifecycle is determining which aspects take the longest, delay other stages, and may lead to better resource utilization without diminishing scientific quality, safety, or the protection of human subjects. In this study, we modeled time-to-event data to explore relationships between clinical trial protocol development and implementation times, as well as to identify potential correlates of prolonged development and implementation. We obtained time interval and participant accrual data from 111 interventional clinical trials initiated between 2006 and 2011 by National Institutes of Health's HIV/AIDS Clinical Trials Networks. We determined the time (in days) required to complete defined phases of clinical trial protocol development and implementation. Kaplan-Meier estimates were used to assess the rates at which protocols reached specified terminal events, stratified by study purpose (therapeutic, prevention) and phase group (pilot/phase I, phase II, and phase III/IV). We also examined several potential correlates to prolonged development and implementation intervals. Even though phase grouping did not determine development or implementation times of either therapeutic or prevention studies, overall we observed wide variation in protocol development times. Moreover, we detected a trend toward phase III/IV therapeutic protocols exhibiting longer developmental (median 2½ years) and implementation times (>3 years). We also found that protocols exceeding the median number of days for completing the development interval had significantly longer implementation. The use of a relatively small set of protocols may have limited our ability to detect differences across phase groupings. Some timing effects present for a specific study phase may have been masked by combining protocols into phase groupings. Presence of informative censoring, such as withdrawal of some protocols from development if they began showing signs of lost interest among investigators, complicates interpretation of Kaplan-Meier estimates. Because this study constitutes a retrospective examination over an extended period of time, it does not allow for the precise identification of relative factors impacting timing. Delays not only increase the time and cost to complete clinical trials but they also diminish their usefulness by failing to answer research questions in time. We believe that research analyzing the time spent traversing defined intervals across the clinical trial protocol development and implementation continuum can stimulate business process analyses and re-engineering efforts that could lead to reductions in the time from clinical trial concept to results, thereby accelerating progress in clinical research.

Building a Protocol Expressway: The Case of Mayo Clinic Cancer Center

Inconsistencies and errors resulting from nonstandard processes, together with redundancies, rework, and excess workload, lead to extended time frames for clinical trial protocol development. This results in dissatisfaction among sponsors, investigators, and staff and restricts the availability of novel treatment options for patients. A team of experts from Mayo Clinic formed, including Protocol Development Unit staff and management from the three Mayo Clinic campuses (Florida, Minnesota, and Arizona), a systems and procedures analyst, a quality office analyst, and two physician members to address the identified deficiencies. The current-state process was intensively reviewed, and improvement steps were taken to accelerate the development and approval of cancer-related clinical trials. The primary goal was to decrease the time from receipt of a new protocol through submission to an approving authority, such as the National Cancer Institute or institutional review board. Using the Define, Measure, Analyze, Improve, Control (DMAIC) framework infused with Lean waste-reduction methodologies, areas were identified for improvement, including enhancing first-time quality and processing new studies on a first-in/first-out basis. The project was successful in improving the mean turnaround time for internally authored protocols (P < .001) from 25.00 weeks (n = 41; range, 3.43 to 94.14 weeks) to 10.15 weeks (n = 14; range, 4.00 to 22.14 weeks). The mean turnaround time for externally authored protocols was improved (P < .001) from 20.61 weeks (n = 85; range, 3.29 to 108.57 weeks) to 7.79 weeks (n = 50; range, 2.00 to 20.86 weeks). DMAIC framework combined with Lean methodologies is an effective tool to structure the definition, planning, analysis, and implementation of significant process changes.

Neo-clinicians, Clinical Trials, and the Reorganization of Medical Research in Paris Hospitals after the Second World War: The Trajectory of Jean Bernard

Neo-clinicians, Clinical Trials, and the Reorganization of Medical Research in Paris Hospitals after the Second World War: The Trajectory of Jean Bernard