Non-clinical Endpoints Research Articles

The learning curve of robotic coronary arterial bypass surgery: A report from the STS database.

There is limited data to inform minimum case requirements for training in robotically assisted coronary artery bypass grafting (RA-CABG). Current recommendations rely on nonclinical endpoints and expert opinion. To determine the minimum number of RA-CABG procedures required to achieve stable clinical outcomes. We included isolated RA-CABG in the Society of Thoracic Surgeons (STS) registry performed between 2014 and 2019 by surgeons without prior RA-CABG experience. Outcomes were approach conversion, reoperation, major morbidity or mortality, and procedural success. Case sequence number was used as a continuous variable in logistic regression with restricted cubic splines with fixed effects. Outcomes were compared between operations performed earlier versus later in case sequences using unadjusted and adjusted metrics. There were 1195 cases performed by 114 surgeons. A visual inflection point occurs by a surgeon's 10th procedure for approach conversion, major morbidity or mortality, and overall procedural success after which outcomes stabilize. There was a significant decrease in the rate of approach conversion (7.7% and 2.5%), reoperation (18.9% and 10.8%), and major morbidity or mortality (21.7% and 12.9%), as well as an increase in the rate of procedural success (72.9% and 85.3%) with increasing experience between groups. In a multivariable logistic regression model, case sequences of >10 were an independent predictor of decreased approach conversion (odds ratio [OR]: 0.27;95% confidence interval [CI]: 0.09-0.84) and increased rate procedural success (OR: 1.96;95% CI: 1.00-3.84). The learning curve for RA-CABG is initially steep, but stable clinical outcomes are achieved after the 10th procedure.

Study design, result posting, and publication of late-stage cardiovascular trials.

Pre-registration of study protocols in accessible databases is required for publication of study results in high-impact medical journals. Nonetheless, data on characteristics of clinical trials registered in these databases and their outcome, in terms of result reporting and publication are limited. We searched for interventional, late-phase cardiovascular disease (CVD) studies in adults registered in Clinicaltrials.gov. first posted after 1 January 2013 and completed up to 31 December 2018. Data on study design, result reporting, and publication were collected, and potential associations with a pre-defined set of explanatory factors were examined. In total, 250 CVD trials were included in the analysis. Of these, 193 (77.2%) were randomized studies, 99 (39.6%) open label designs, and 126 (50.4%) had industry as main sponsor. One hundred and seventy-nine trials (71.6%) evaluated the effect of drugs and 27 (10.8%) evaluated devices. The most common primary outcomes were non-clinical endpoints (76.0%), with only 17% of studies evaluating clinical endpoints. Industry-funded trials focused on patent-protected drugs and devices more often than non-industry-funded trials (72.0% vs. 30.6%, P < 0.001 and 55.0% vs. 26.3%, P = 0.033, respectively). Sixty-three studies (25.2%) had results posted on clinicaltrials.gov, and 116 (46.4%) had results published in the scientific literature. In multivariate analysis, industry sponsorship was statistically significantly associated with results posting [odds ratio (OR): 3.38; 95% confidence interval (CI): 1.56-7.30, P = 0.002] and publication (OR: 0.41; 95% CI: 0.23-0.75, P = 0.004). Among late-stage cardiovascular trials only one-fourth had results posted on clinicaltrials.gov and <50% had results published. Industry sponsors were more likely to invest in research on patent-protected drugs and devices than were non-industry sponsors. Industry-sponsored studies were more likely to have their results posted, but less likely to have their results published in the scientific literature.

Magnesium: A Magic Bullet for Cardiovascular Disease in Chronic Kidney Disease?

Magnesium is essential for many physiological functions in the human body. Its homeostasis involves dietary intake, absorption, uptake and release from bone, swifts between the intra- and extracellular compartment, and renal excretion. Renal excretion is mainly responsible for regulation of magnesium balance. In chronic kidney disease (CKD), for a long time the general policy has been limiting magnesium intake. However, this may not be appropriate for many patients. The reference ranges for magnesium are not necessarily optimal concentrations, and risks for insufficient magnesium intake exist in patients with CKD. In recent years, many observational studies have shown that higher (in the high range of “normal” or slightly above) magnesium concentrations are associated with better survival in CKD cohorts. This review gives an overview of epidemiological associations between magnesium and overall and cardiovascular survival in patients with CKD. In addition, potential mechanisms explaining the protective role of magnesium in clinical cardiovascular outcomes are described by reviewing evidence from in vitro studies, animal studies, and human intervention studies with non-clinical endpoints. This includes the role of magnesium in cardiac arrhythmia, heart failure, arterial calcification, and endothelial dysfunction. Possible future implications will be addressed, which will need prospective clinical trials with relevant clinical endpoints before these can be adopted in clinical practice.

Quality Indicators for Evaluating Prehospital Emergency Care: A Scoping Review.

A scoping review was conducted through a search of PubMed (National Center for Biotechnology Information, National Institutes of Health; Bethesda, Maryland USA); EMBase (Elsevier; Amsterdam, Netherlands); CINAHL (EBSCO Information Services; Ipswich, Massachusetts USA); Web of Science (Thomson Reuters; New York, New York USA); and the Cochrane Library (The Cochrane Collaboration; Oxford, United Kingdom). To increase the sensitivity of the literature, a search of the grey literature and review of select websites was additionally conducted. Articles were selected that proposed at least one PEC QI and whose aim was to discuss, analyze, or promote quality measurement in the PEC environment. The majority of research (n=25 articles) was published within the last decade (68.0%) and largely originated within the USA (68.0%). Delphi and observational methodologies were the most commonly employed for QI development (28.0%). A total of 331 QIs were identified via the article review, with an additional 15 QIs identified via the website review. Of all, 42.8% were categorized as primarily Clinical, with Out-of-Hospital Cardiac Arrest contributing the highest number within this domain (30.4%). Of the QIs categorized as Non-Clinical (57.2%), Time-Based Intervals contributed the greatest number (28.8%). Population on Whom the Data Collection was Constructed made up the most commonly reported QI component (79.8%), followed by a Descriptive Statement (63.6%). Least reported were Timing of Data Collection (12.1%) and Timing of Reporting (12.1%). Pilot testing of the QIs was reported on 34.7% of QIs identified in the review. Overall, there is considerable interest in the understanding and development of PEC quality measurement. However, closer attention to the details and reporting of QIs is required for research of this type to be more easily extrapolated and generalized. Howard I , Cameron P , Wallis L , Castren M , Lindstrom V . Quality indicators for evaluating prehospital emergency care: a scoping review. Prehosp Disaster Med. 2018;33(1):43-52.

Developing and utilizing controlled human models of infection.

The controlled human infection model (CHIM) to assess the efficacy of vaccines against Shigella and enterotoxigenic Escherichia coli (ETEC) has several unique features that could significantly enhance the ability to test candidate vaccines. Despite increasing interest in these models, questions remain as to how to best incorporate them into vaccine development and how to maximize results. We designed a workshop focused on CHIM as part of the Vaccines Against Shigella and ETEC (VASE) Conference. The workshop, using the World Café method, focused on; clinical outcomes, nonclinical outcomes and model standardization. Researchers with a variety of expertise and experience rotated through each focus area and discussed relevant sub-topics. The results of these discussions were presented and questions posed to guide future workshops. Clinical endpoint discussions focused on the need for harmonized definitions; optimized attack rates; difficulties of sample collection and a need for non-stool based endpoints. Nonclinical discussions centered on evolving omics-based opportunities, host predictors of susceptibility and novel characterizations of the immune response. Model standardization focused on the value of shared procedures across institutions for clinical and non-clinical endpoints as well as for strain preparation and administration and subject selection. Participants agreed CHIMs for Shigella and ETEC vaccine development could accelerate vaccine development of a promising candidate; however, it was also appreciated that variability in the model and our limited understand of the host-pathogen interaction may yield results that could negatively impact a suitable candidate. Future workshops on CHIM are needed to ensure the optimal application of these models moving forward.

Abstract 2602: The nonclinical toxicology profile of pacritinib, a JAK2/FLT3 inhibitor with no dose-limiting clinical myelosuppression

Abstract Pacritinib is an orally active kinase inhibitor being developed for the treatment of myelofibrosis (MF). Pacritinib is a particularly potent inhibitor of wild-type and mutant isoforms of JAK2 and FLT3 (IC50 values &amp;lt; 15 nM), and it does not suppress JAK1 at clinically relevant concentrations. Additional kinases targeted by pacritinib include IRAK1 (IC50 = 13.6 nM) and c-fms (or CSF1R; IC50 = 39.5 nM). Pacritinib is pharmacologically active in nonclinical tumor models driven by JAK2 or FLT3 overexpression, and clinical trials have demonstrated that pacritinib can ameliorate symptoms in MF patients. A key differentiating feature of pacritinib over currently available JAK2 inhibitors is its lack of dose-limiting clinical myelosuppression, allowing for treatment of patients with cytopenias. The comparatively reduced myelosuppressive activity of pacritinib is thought to be due to its lack of pharmacological activity on JAK1, and/or its inhibition of IRAK1 and c-fms, which may contribute to anti-inflammatory activity. Nonclinical pacritinib data from rodent and canine studies were evaluated in comparison to publicly available information for other JAK2 inhibitors to determine if differences in nonclinical endpoints might correlate with the observed clinical differences in myelosuppressive effects. The qualitative nonclinical findings seen in rodents were similar for all JAK2 inhibitors, and included decreases in leukocytes, red cell mass, and reticulocytes; lymphoid depletion in the spleen, thymus, and/or lymph nodes; and hypocellularity of the bone marrow. Interestingly, platelet decreases were not observed in rodent or canine nonclinical models, even with JAK2 inhibitors associated with clinical thrombocytopenia. However, in the dog, pacritinib is unique for its minimal myelosuppressive effects in the pivotal 30-day and 39-week studies, despite being performed at higher exposure levels relative to other similar JAK2 inhibitor studies. With pacritinib, non-adverse lymphoid reduction was seen in the spleen, lymph nodes, Peyer's patches, and/or thymus; but there were no clinical pathology findings indicative of marked myelosuppression, nor were there any treatment-related findings in detailed bone marrow evaluations. Overall, these comparisons suggest that nonclinical bone marrow data and clinical pathology in the dog may be informative endpoints for estimating the myelosuppressive potential of JAK2 inhibitors in the clinic. Citation Format: Rebecca Watson, Suliman Al-Fayoumi. The nonclinical toxicology profile of pacritinib, a JAK2/FLT3 inhibitor with no dose-limiting clinical myelosuppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2602.

Risk Management Plans in the European Union: Nonclinical Aspects.

Within the European Union (EU) there is a requirement to submit a risk management plan (RMP) for a proposed new drug at the time of submission of the Marketing Authorisation Application (MAA). An RMP may also be needed for existing products when there is a significant change to the MAA. Although regulatory guidance is available to help frame what nonclinical data need to be discussed in the RMP, there is little information available on what is considered to be appropriate content. However, the presentation and discussion of generated nonclinical data, and whether any of the study findings pose an actual or potential safety concern for human use, forms a vital component of the RMP. To confirm this situation, data from centrally authorized products in the EU show that the majority of those with a published RMP summary contain information concerning nonclinical aspects of development. This article provides information to aid in the decision making of appropriate nonclinical content in the RMP and highlights the most common nonclinical endpoints discussed in published RMP summaries both as Identified or Potential Risks and as Planned Studies to further evaluate the risk.

Impact of routine manual aspiration thrombectomy on outcomes of patients undergoing primary percutaneous coronary intervention for acute myocardial infarction: A meta-analysis

BackgroundThe efficacy and safety of thrombectomy as an adjunct to primary percutaneous intervention (PCI) in the management of acute myocardial infarction (AMI) are debated. We performed a meta-analysis of randomized trials comparing primary PCI performed with versus without routine aspiration thrombectomy (AT). MethodsA meta-analysis of randomized AT trials reporting clinical outcomes was done in accordance with the PRISMA guidelines. Trials reporting only non-clinical endpoints and those of technologies other than manual devices were excluded. The primary endpoint of this meta-analysis was mortality (either all-cause or cardiovascular). Secondary endpoints were reinfarction, stent thrombosis, and stroke. ResultsSeventeen randomized trials, involving 20,853 patients were included. Weighted mean follow-up was 9.3±3.3months. The rates of all-cause mortality (reported in 14 trials, n=10,430) and cardiovascular mortality (reported in 6 trials, n=11,810) did not differ significantly between patients treated with or without AT (4.6% vs. 5.3%, RR=0.88 [95%CI=0.75–1.04]; and, 3.0% vs. 3.7%, RR=0.83 [95%CI=0.68–1.01]; respectively). The rates of reinfarction and stent thrombosis were also similar in patients treated with versus those treated without AT (2.1% vs. 2.2%; RR=0.96 [95%CI=0.80–1.15]; and, 1.2% vs. 1.4%; RR=0.84 [95%CI=0.65–1.07], respectively). However, stroke rates were increased with AT (0.84% vs. 0.52%, RR=1.56 [95%CI=1.09–2.25]). ConclusionsRoutine AT as an adjunct to primary PCI does not reduce the rates of death, reinfarction, or stent thrombosis, but is associated with increased stroke risk.

Acute surgical unit: the Australasian experience

The acute surgical unit (ASU) model of care is a new paradigm shift in the provision of emergency surgery. Clinical and non-clinical outcomes have been described after the introduction of the ASU model in Australia and New Zealand. This paper reviews and analyses the current published literature and methods of implementation of contemporary ASU models. We conducted a comprehensive database search to identify all relevant published papers pertaining to the ASU. Included papers compared ASU models to emergency surgery's traditional model of care. Relevant clinical and non-clinical end points were extracted for analysis. Seven papers and two abstracts published data assessing clinical and non-clinical end points within the ASU. Four out of six studies reported a reduction in hospital length of stay. Two out of three studies showed reduction in mean time to emergency department review and two out of four studies reported a reduction in time to surgery. Additionally, four out of five studies showed a reduction in after hours operating with an ASU model. Trends in clinical outcomes are seen including reduced length of stay, time to emergency department assessment and surgery, supplemented by non-clinical outcomes including reduced after hours operating and the potential for increased training opportunities. The published data presents certain weaknesses and further information is required to appreciate the applicability of certain aspects of the ASU model to smaller centres.

Fusion of nonclinical and clinical data to predict human drug safety

Adverse drug reactions continue to be a major cause of morbidity in both patients receiving therapeutics and in drug R&D programs. Predicting and possibly eliminating these adverse events remains a high priority in industry, government agencies and healthcare systems. With small molecule candidates, the fusion of nonclinical and clinical data is essential in establishing an overall system that creates a true translational science approach. Several new advances are taking place that attempt to create a ‘patient context’ mechanism early in drug research and development and ultimately into the marketplace. This ‘life-cycle’ approach has as its core the development of human-oriented, nonclinical end points and the incorporation of clinical knowledge at the drug design stage. The next 5 years should witness an explosion of what the author views as druggable and safe chemical space, pharmacosafety molecular targets and the most important aspect, an understanding of unique susceptibilities in patients developing adverse drug reactions. Our current knowledge of clinical safety relies completely on pharmacovigilance data from approved and marketed drugs, with a few exceptions of drugs failing in clinical trials. Massive data repositories now and soon to be available via cloud computing should stimulate a major effort in expanding our view of clinical drug safety and its incorporation into early drug research and development.

Establishment of an aerosol challenge model of tuberculosis in rhesus macaques and an evaluation of endpoints for vaccine testing.

The establishment of an aerosol challenge model in nonhuman primates (NHPs) for the testing of vaccines against Mycobacterium tuberculosis would assist the global effort to optimize novel vaccination strategies. The endpoints used in preclinical challenge studies to identify measures of disease burden need to be accurate and sensitive enough to distinguish subtle differences and benefits afforded by different tuberculosis (TB) vaccine regimens when group sizes are inevitably small. This study sought to assess clinical and nonclinical endpoints as potentially sensitive measures of disease burden in a challenge study with rhesus macaques by using a new protocol of aerosol administration of M. tuberculosis. Immunological and clinical readouts were assessed for utility in vaccine evaluation studies. This is the first example of TB vaccine evaluation with rhesus macaques where long-term survival was one of the primary endpoints. However, we found that in NHP vaccine efficacy studies with maximum group sizes of six animals, survival did not provide a valuable endpoint. Two approaches used in human clinical trials for the evaluation of the gamma interferon (IFN-gamma) response to vaccination (enzyme-linked immunospot [ELISpot] assay and enzyme-linked immunosorbent assay [ELISA]) were included in this study. The IFN-gamma profiles induced following vaccination were found not to correlate with protection, nor did the level of purified protein derivative (PPD)-specific proliferation. The only readout to reliably distinguish vaccinated and unvaccinated NHPs was the determination of lung lesion burden using magnetic resonance (MR) imaging combined with stereology at the end of the study. Therefore, the currently proposed key markers were not shown to correlate with protection, and only imaging offered a potentially reliable correlate.

Adolescents with Hodgkin Lymphoma Treated on Adult and Pediatric Protocols Have Distinct Therapeutic Outcome.

Hodgkin Lymphoma (HL) is a B cell malignancy, highly curable in the modern era (1989–2004). It is the most common cancer in the 15–19 age range. In the United States, adolescents with de novo HL may be treated on either pediatric or adult protocols. To identify outcomes of adolescents with HL, we conducted a comprehensive literature review and statistical analysis of all treatment trials (N > 50 pts) published in the past 15 years. Trials were selected for their relevance to treatment and disease outcome in adolescents with the following search criteria: Hodgkins disease, therapy, treatment, adolescents (13–18 years), and adults (19–44 years). The search retrieved 120 randomized control trials and 57 Phase II trials. 117 trials were eliminated due to inappropriate histology, non-clinical endpoints, topic reviews or otherwise not meeting established criteria. 79 studies were eligible for analysis. 15 pediatric treatment protocols (13 multi-center, 7 randomized) met established criteria. 7 identified the number of adolescents on trial (N=958/2675; 36%). Only 3 of these studies evaluated adolescent outcome; one trial demonstrated an inferior event-free survival for the adolescent subgroup vs. all children (72.0% vs. 89.0%; p-value 0.006, Chi Square Test). 57 adult treatment studies (39 multi-center, 44 randomized) were reviewed. 7 identified the number of adolescents on trial (N=422/2522; 17%). Only one provided information on adolescent outcome, which experienced a superior overall survival compared with the entire population (86.0% vs. 73.1%; p-value 0.030, Chi Square Test). None of the trials with both pediatric and adult subjects (7 multi-center, 4 randomized) provided information on the adolescent subgroup. In comparing pediatric and adult trials, we found remarkable differences in therapeutic approaches (all pediatric studies included XRT as a treatment component compared to 58% of adult studies) and in trial design (77% of adult studies were randomized compared to 47% of pediatric studies; p-value 0.0234, Fishers Exact Test). The adolescent population with HL is significantly understudied despite reasonable clinical trial participation and relatively high prevalence. In fact, only 4 published trials provided outcome information on adolescents with HL; in 2, outcome was statistically different from the rest of the study population, suggesting this subgroup may benefit from a specialized treatment approach. It is critical for future treatment trials to analyze results of the adolescent population to determine whether unique biological features, therapeutic practices, or host factors contribute to prognosis and outcome.

Conduct disorder: guidelines for investigating efficacy of pharmacological intervention

The controlled human infection model (CHIM) to assess the efficacy of vaccines against Shigella and enterotoxigenic Escherichia coli (ETEC) has several unique features that could significantly enhance the ability to test candidate vaccines. Despite increasing interest in these models, questions remain as to how to best incorporate them into vaccine development and how to maximize results. We designed a workshop focused on CHIM as part of the Vaccines Against Shigella and ETEC (VASE) Conference.The workshop, using the World Café method, focused on; clinical outcomes, nonclinical outcomes and model standardization. Researchers with a variety of expertise and experience rotated through each focus area and discussed relevant sub-topics. The results of these discussions were presented and questions posed to guide future workshops.Clinical endpoint discussions focused on the need for harmonized definitions; optimized attack rates; difficulties of sample collection and a need for non-stool based endpoints. Nonclinical discussions centered on evolving omics-based opportunities, host predictors of susceptibility and novel characterizations of the immune response. Model standardization focused on the value of shared procedures across institutions for clinical and non-clinical endpoints as well as for strain preparation and administration and subject selection.Participants agreed CHIMs for Shigella and ETEC vaccine development could accelerate vaccine development of a promising candidate; however, it was also appreciated that variability in the model and our limited understand of the host-pathogen interaction may yield results that could negatively impact a suitable candidate. Future workshops on CHIM are needed to ensure the optimal application of these models moving forward.