How Informative were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov

Background Early in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic. Methods We created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/). Results We included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7-36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%. Conclusions Less than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

Diagnosis and Management of Radiation Necrosis in Patients with Brain Metastases and Primary Tumors

The incidence of radiation necrosis has increased secondary to combined modality therapy for brain tumors and stereotactic radiosurgery. The pathology of progressive brain radiation necrosis (RN) primarily includes inflammation and angiogenesis in which cytokines, chemokines, and vascular endothelial growth factors are upregulated. Combined multiparametric imaging, including lesional metabolism, spectroscopy, and blood flow, could enhance diagnostic accuracy compared with a single imaging study. Nevertheless, a substantial risk of bias restricts firm conclusions about the best imaging technique for diagnosing brain RN. Bevacizumab shows promising results of improving radiographic edema and post-gadolinium enhancement with associated symptomatic improvement. However, this was based on small double-blinded randomized controlled trials, which introduces a high risk of bias due to the small sample size despite the high-quality trial design. Edaravone combined with corticosteroids also resulted in a more significant reduction in radiographic edema than corticosteroids alone but had no impact on reducing the enhancing lesion. There is a great need for further prospective randomized controlled trials (RCTs) to treat brain RN.

Evidence-Based Guidelines Should Be Used to Inform COVID-19 Management

A recent commentary by McCullough (1) includes a recommended COVID treatment algorithm that is outdated and parts of which are contradicted by high quality trial data.…

Protocol of the Development of a Core Outcome Set for Ischemic Stroke in Clinical Trials of Chinese Medicine

Background. Ischemic stroke (IS) seriously impacts the quality of life of survivors. Chinese medicine (CM) has been developed for more than 2000 years and plays a key role in the treatment of ischemic stroke. Many Chinese medicine clinical trials have been conducted; however, the heterogeneity of outcome measurements and reporting limits implications of the findings in clinical practice and health policy development. Therefore, it is important to develop a core outcome set (COS) that should be used and reported in trials for ischemic stroke treated by Chinese medicine. This protocol describes the process of developing the IS-CM-COS. Methods and Analysis. The development of the COS will involve the following four steps: (1) A list of outcomes reported in the registered and published Chinese medicine trials of ischemic stroke will be extracted by conducting a systematic literature review. (2) An additional outcome list will be collected by semistructured interview to patients with ischemic stroke. (3) A two-round Delphi survey will be performed to prioritize and condense the outcomes. (4) In the consensus meeting, a final recommended COS will be developed. Discussion. The COS could improve the reliability and consistency of outcome reporting. We hope that this IS-CM-COS will be used in the future Chinese medicine trials for the treatment of ischemic stroke and improve research quality. Trial Registration. This study was registered with the Core Outcome Measures in Effectiveness Trials Initiative (http://www.comet-initiative.org/studies/details/1282).

Investigation-Based Drug Value Framework in Hodgkin Lymphoma

Background Currently available drug value frameworks integrate data about a medication's benefits and risks. However, the strength of the research data supporting the use of one medication versus another is highly variable. The greater the number and quality of well-conducted trials underlying a certain intervention, the stronger its potential favorable contribution to public health. Drug value should therefore also be a function of the magnitude of clinical evidence gleaned from high-quality clinical trials. Methods We propose an investigation-driven value framework that determines the merit of a drug based on the overall available evidence, including the rigour of relevant trials. The NCCN Hodgkin Lymphoma guidelines were reviewed and data collected about commonly used regimens for Classic HL. Value scores were determined for each drug combination. Results A model was designed incorporating information about the number of RCTs conducted, the total number of participants enrolled, and the generalizability to real-world populations, in addition to the drug's efficacy, significant toxicity and cost (Figure 1). Practice-changing trials supporting each of the currently-endorsed regimens were collected from the HL NCCN guidelines (ABVD, 4; Stanford V 4; Esc BEACOPP 2). The average number of participants per trial was higher for ABVD (1,126) and Esc BEACOPP (1,890) than for Stanford V (267). The generalizability score for the three compounds was 0.5 (ABVD), 0.25 (Stanford V) and -1 (Esc BEACOPP). The mean 5-year overall survival rate was higher in the case of ABVD (96.2%) and Esc BEACOPP (96.1%) compared with Stanford V (92.0%). The toxicity score was 1.24 (ABVD), 3 (Stanford V) and 2.5 (Esc BEACOPP). Using a multi-factorial value scoring system, ABVD, Esc BEACOPP and Stanford V obtained 11.5, 9.5 and 8.5 points, respectively. A scoring system that focused on traditional factors alone (efficacy, toxicity, cost) yielded different scores (ABVD, 7.7; Stanford V 6.7; Esc BEACOPP, 6.5). Conclusion The robustness of clinical trials investigating anti-cancer regimens deserves special consideration when defining drug value. Three high-quality trial characteristics help stratify common regimens in HL into higher/lower value strata using a simple, easy to use algorithm. Disclosures No relevant conflicts of interest to declare.

A Review of Ginseng Clinical Trials Registered in the WHO International Clinical Trials Registry Platform

Although ginseng has long been broadly used in clinical settings around the world, few clinical trials on ginseng have been conducted. The objective of this study was to provide a comprehensive evaluation of the characteristics of ginseng clinical trials registered in the WHO International Clinical Trials Registry Platform (ICTRP) as of December 2017 regarding their frequency, design, type of ginseng, dosage, duration, condition, funding sources, and publication status. A total of 134 ginseng clinical studies were registered from 2002 to 2017, of which 60.4% were completed and 23.1% are actively recruiting participants. A large number of trials were associated with aspects of high-quality trial design. Overall, 94% of the trials employed randomized allocation to study arms, 78.4% were double-blind studies using placebo as one of the control groups, and 71% were published as completed trials. Trials whose sample size was restricted to fewer than 100 participants accounted for 74.7% of the total. Of the primary funding sources for ginseng studies, 67.2% were nonindustry organizations. The ginseng clinical trials were heterogeneous with respect to ginseng species and variety, indications, dose, duration, and participant characteristics. Clearly, stricter and methodologically suitable studies are needed to demonstrate the efficacy and safety of ginseng.

TransCelerate: a global collaboration across biopharmaceutical R&D to accelerate and simplify new medi-cines development

As the economic pressures increase on healthcare systems around the world due to aging populations, chronic diseases, expanding patient populations in emerging markets and advances in medical technology, it is crucial that we focus on developing and delivering innovative and quality medicines with true medical value to patients around the world in a more collaborative, quality-focused and cost-effective manner.An important component to this mission across the biopharmaceutical industry is identifying and solving common issues that compromise the success of a clinical development program – the shared pathway to safer and more clinically meaningful medicines. However, subject recruitment challenges, data collection and follow-up issues, identification of high-quality trial sites, and lack of successfully achieving study timelines continue to stress clinical trial operations teams across companies. Although there has been progressing across this range of roadblocks by individual companies, the underlying economics continue to threaten the research and development (R&D) business model.Failure to solve these key issues will affect all parties involved in the clinical trial enterprise: patients, clinical inves-tigators, health authorities, academia, tax-payers and the sponsor companies. The question remains whether a deep and broad collaborative effort that stretches across the clinical development arena—one that is charged with a common goal of improving quality, enhancing the investigator and patient experience, reducing costs and sharing data—can be a catalyst for success. With encouraging signs already realised, the operation of TransCelerate BioPharma Inc., a non-profit organisation created to improve the health of people around the world by accelerating and enhancing the R&D of innovative new therapies will test this premise.

Yield and quality performances of four tea test clones

An experiment was carried out during 1994–2007 to investigate the yield and quality performances of four vegetatively propagated test clones of tea viz. SH/D/11/13, SH/D/11/333, B/HB/2/3 and B/HB/6/4. Two clones, BT1 and TV23, were used as check for quality and yield, respectively. Cuttings of the test clones were collected from the selected bushes of Shumshernugger Tea Estate and hybrid lines of Bangladesh Tea Research Institute (BTRI) and were raised at BTRI nursery. Then the saplings were managed for long term yield and quality trial following randomized complete block design with 5 replications. The green leaf was harvested at weekly interval during the plucking season starting from mid March to mid December throughout the experimental period. The overall cup quality of the test clones was assessed by conventional organoleptic test. At the immature stage (2nd–5th year after plantation), all test clones showed similar yield trend as that of check BT1. At the mature stage (6th–13th year), the test clones SH/D/11/333 and B/HB/6/4 gave the significantly higher average yield (3095 and 3342 kg ha–1 made tea, respectively) compared to the check BT1 (3042 kg ha–1 made tea). The cup quality of all the test clones and BT1 was found to be “Above Average” while the cup quality of TV23 was “Average”. Considering the overall performances, the test clones SH/D/11/333 and B/HB/6/4 have been released as BT13 and BT14, respectively for commercial plantation in the tea estates. DOI: http://dx.doi.org/10.3329/jbau.v10i1.12036 J. Bangladesh Agril. Univ. 10(1): 33–38, 2012