Phase IV Drug Trials With a Canadian Site: A Comparison of Industry and Non-Industry-Funded Trials.

Recent regulatory reforms have favored expedited drug marketing and increased reliance on Phase IV clinical trials for safety and efficacy assurance. This study, utilizing ClinicalTrials.gov, assesses the characteristics of Phase IV trials, with at least one site in Canada, examing those funded by industry sponsors and those lacking industry funding. Additionally, it compares the publication status of industry-funded and non-industry-funded trials through a manual review of the medical literature. Between 2000 and 2022, 864 Phase IV trials were completed, with 480 (55.6%) receiving industry funding and 384 (44.4%) funded solely by non-industry sources. Industry-funded clinical trials were larger (mean 204 enrollees versus 70), more likely to be international (57.7% versus 9.6%) and reported results more promptly (1.21 years after completion versus 1.85 years), yet both types shared similar design, outcomes, and completion time. Publication rates were 81.8% for industry-funded and 65.8% for non-industry-funded trials. The ClinicalTrials.gov registry displayed 48 inaccuracies in publication associations, raising concerns about its accuracy. Our findings underscore the existing institutional limitations in ensuring comprehensive reporting and publication of Phase IV trial results funded by both industry and non-industry sources.

Clinical practice guideline recommendations to improve the mental health of adult trauma patients: protocol for a systematic review.

INTRODUCTION: Mental disorders are common in adult patients with traumatic injuries. To limit the burden of poor psychological well-being in this population, recognised authorities have issued recommendations through clinical practice guidelines (CPGs). However, the uptake of evidence-based recommendations to improve the mental health of trauma patients has been low until recently. This may be explained by the complexity of optimising mental health practices and interpretating CGPs scope and quality. Our aim is to systematically review CPG mental health recommendations in the context of trauma care and appraise their quality. METHODS AND ANALYSIS: We will identify CPG through a search strategy applied to Medline, Embase, CINAHL, PsycINFO and Web of Science databases, as well as guidelines repositories and websites of trauma associations. We will target CPGs on adult and acute trauma populations including at least one recommendation on any prevention, screening, assessment, intervention, patient and family engagement, referral or follow-up procedure related to mental health endorsed by recognised organisations in high-income countries. No language limitations will be applied, and we will limit the search to the last 15 years. Pairs of reviewers will independently screen titles, abstracts, full texts, and carry out data extraction and quality assessment of CPGs using the Appraisal of Guidelines Research and Evaluation (AGREE) II. We will synthesise the evidence on recommendations for CPGs rated as moderate or high quality using a matrix based on the Grading of Recommendations Assessment, Development and Evaluation quality of evidence, strength of recommendation, health and social determinants and whether recommendations were made using a population-based approach. ETHICS AND DISSEMINATION: Ethics approval is not required, as we will conduct secondary analysis of published data. The results will be disseminated in a peer-reviewed journal, at international and national scientific meetings. Accessible summary will be distributed to interested parties through professional, healthcare quality and persons with lived experience associations. PROSPERO REGISTRATION NUMBER: (ID454728).

Level of implementation of pain management and early mobilization strategies to prevent delirium in geriatric trauma patients: A mixed-methods study.

BACKGROUND: Pain management and early mobilization strategies are recommended in clinical practice guidelines for the prevention of delirium in older adults. However, available data on the implementation of these strategies in trauma are limited. AIMS: To describe the use of pain management and early mobilization strategies in older adults at a level I trauma center, as well as the facilitators and barriers to their implementation. METHODS: A convergent mixed methods study was used. Quantitative data were collected from sixty medical records. Qualitative data was collected through a focus group with healthcare providers to explore their perspectives regarding the use of the target practices and on barriers and facilitators to their implementation. Descriptive statistics were calculated, and a thematic analysis using an inductive and deductive interpretative descriptive approach was undertaken. RESULTS: A question on the presence/absence of pain was the most frequently documented pain assessment method. Pain assessment was poorly documented. Frequencies of non-opioid and opioid administrations were similar, but non-pharmacological strategies were not widely used. The first mobilization was performed quickly and was most commonly to a chair. The focus group discussion confirmed many of the data collected in the medical records. Barriers to implementing the targeted strategies were primarily related to organizational context and facilitation processes. CONCLUSIONS: Areas for improvement were identified including pain assessment, the use of non-pharmacological pain management strategies and ambulation as a mobilization strategy. Our findings will serve as a starting point for optimizing and adapting practices for geriatric trauma patients and evaluating their impact.

Correction: Whose shoulders is health research standing on? Determining the key actors and contents of the prevailing biomedical research agenda.

[This corrects the article DOI: 10.1371/journal.pone.0249661.].

Prevalence and nature of manufacturer-sponsored patient support programs for prescription drugs in Canada: a cross-sectional study.

BACKGROUND: Globally, pharmaceutical companies offer patient support programs in tandem with their products, which aim to enhance medication adherence and patient experience through education, training, support and financial assistance. We sought to identify the proportion and characteristics of such patient support programs in Canada and to describe the nature of supports provided. METHODS: We conducted a crosssectional study to identify and characterize all marketed prescription drugs available in Canada as of Aug. 23, 2022, using the Health Canada Drug Product and CompuScript databases. To describe the nature of supports provided, we conducted a content analysis of publicly available patient support program websites and Web-based documents. Using logistic regression, we identified characteristics of drugs associated with having a patient support program including brand-name or branded generic (generic medications with a proprietary name), orphan (medications for rare diseases) or biologic drug status; estimated total cost of prescriptions dispensed at retail pharmacies; and price per unit. RESULTS: Of the 2556 prescription drugs marketed by 89 companies in the study period, 256 (10.0%) had a patient support program in Canada. Many of the 89 drug manufacturers (n = 55, 61.8%) offered at least 1 patient support program, frequently relying on third-party administrators for delivery. Brandname and branded generic medications, biologic agents and drugs with orphan status were more likely to have a patient support program than generic drugs. Compared with drugs priced $1.01-$10.00 per unit, drugs priced $10.01-$100.00 per unit were nearly 8 times more likely to have a patient support program (adjusted odds ratio 7.54, 95% confidence interval 4.07- 14.64). Most sampled patient support programs included reimbursement navigation (n = 231, 90.2%) and clinical case management (n = 223, 87.1%). INTERPRETATION: About 1 in 10 drugs marketed in Canada has a manufacturersponsored patient support program, but these are concentrated around brand-name, branded generic, biologic and high-cost drugs, often for rare diseases. To understand the impact of patient support programs on health outcomes and sustainable access to cost-effective medicines, greater transparency and independent evaluation of patient support programs is necessary.

Educational needs and preferences of adult patients with acute or chronic pain: a mixed methods systematic review protocol.

OBJECTIVES: This review will aim to synthesize the available quantitative and qualitative evidence on the educational needs and preferences of adult patients with acute or chronic pain. INTRODUCTION: Acute and chronic pain are prevalent problems and are associated with significant individual and societal consequences. Education is a critical component of pain management. However, the impact of educational interventions on pain outcomes remains limited. The lack of patient input--what patients want to know and how they want to be informed--is one of the main issues underlying intervention design. INCLUSION CRITERIA: We will include qualitative, quantitative, and mixed methods studies describing the educational needs and preferences of adult patients with acute or chronic pain. METHODS: This review will follow the JBI guidelines for mixed methods systematic reviews. We will search MEDLINE (PubMed), Embase (Ovid), PsycINFO (Ovid), CINAHL (EBSCO), the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and ProQuest Dissertations and Theses. The search strategy will commence from the year 1990 onward and there will be no language restrictions. The retrieved titles, abstracts, and full-text reports will be screened by pairs of independent reviewers. These pairs of reviewers will also independently extract data using the JBI tools for mixed methods systematic reviews. Methodological quality will be assessed using the mixed methods appraisal tool. A convergent integrated approach to synthesis and integration of the quantitative and qualitative data will be used. REVIEW REGISTRATION: PROSPERO CRD42022303834.

Identifying Quality Indicators for the Care of Hospitalized Injured Older Adults: A Scoping Review of the Literature.

OBJECTIVES: Older adults represent more than 50% of trauma admissions in many high-income countries. Furthermore, they are at increased risk for complications, resulting in worse health outcomes than younger adults and a significant health care utilization burden. Quality indicators (QIs) are used to assess the quality of care in trauma systems, but few QIs reflect responses to older patients' specific needs. We aimed to (1) identify QIs used to assess acute hospital care for injured older patients, (2) assess support for identified QIs and, (3) identify gaps in existing QIs. DESIGN: Scoping review of the scientific and gray literature. METHODS: Selection and data extraction were performed by 2 independent reviewers. The level of support was assessed by the number of sources reporting QIs and whether they were developed according to scientific evidence, expert consensus, and patients' perspectives. RESULTS: Of 10,855 identified studies, 167 were eligible. Among 257 different QIs identified, 52% were hip fracture specific. Gaps were identified for head injuries, rib, and pelvic ring fractures. Although 61% of QIs assessed care processes, 21% and 18% focused on structures and outcomes, respectively. Although most QIs were based on literature reviews and/or expert consensus, patients' perspective was rarely accounted for. The 15 QIs with the highest level of support included minimum time between emergency department arrival and ward admission, minimum time to surgery for fractures, assessment by a geriatrician, orthogeriatric review for hip fracture patients, delirium screening, prompt and appropriate analgesia, early mobilizations, and physiotherapy. CONCLUSION AND IMPLICATIONS: Multiple QIs were identified, but their level of support was limited, and important gaps were identified. Future work should focus on achieving consensus for a set of QIs to assess the quality of trauma care to older adults. Such QIs could be used for quality improvement and ultimately improve outcomes for injured older adults.

Commentary: Reconsidering Pharmaceutical Research and Development Investments.

Following Lee and colleagues' (2023) article explaining how Canadians are being shortchanged by drug companies when it comes to investments in research and development (R&D), this rejoinder adds context and appends two other very problematic elements in the debate between wishful narratives over the industry's contribution in R&D and actual numbers. First, even the current stricter definition of R&D investment might simply be too large considering that elements such as seeding trials - a well-known marketing device - can be accounted for as R&D expenditures. Second, this rejoinder identifies how Statistics Canada acted in concert with Innovative Medicines Canada to reinforce the industry's preferred narratives around R&D expenditures. This situation puts into question the trustworthiness of Canada's statistical agency.

Interdisciplinary strategies to prevent long-term and detrimental opioid use following trauma: a stakeholder consensus study.

OBJECTIVE: Prolonged opioid use is common following traumatic injuries. Although preventive strategies have been recommended, the evidence supporting their use is low. The objectives of this study were to select interdisciplinary strategies to prevent long-term, detrimental opioid use in trauma patients for further evaluation and to identify implementation considerations. DESIGN: A consensus study using the nominal group technique. SETTING: Four trauma systems in Canada. SUBJECTS: Participants included expert clinicians and decision makers, and people with lived experience. METHODS: Participants had to discuss the relevance and implementation of 15 strategies and then rank them using a 7-point Likert scale. Implementation considerations were identified through a synthesis of discussions. RESULTS: A total of 41 expert stakeholders formed the nominal groups. Overall, eight strategies were favored: 1) using multimodal approach for pain management, 2) professional follow-up in physical health, 3) assessment of risk factors for opioid misuse, 4) physical stimulation, 5) downward adjustment of opioids based on patient recovery, 6) educational intervention for patients, 7) training offered to professionals on how to prescribe opioids, and 8) optimizing communication between professionals working in different settings. Discussions with expert stakeholders revealed the rationale for the selected strategies and identified issues to consider when implementing them. CONCLUSION: This stakeholder consensus study identified, for further scientific study, a set of interdisciplinary strategies to promote appropriate opioid use following traumatic injuries. These strategies could ultimately decrease the burden associated with long-term opioid use.

Poisoning Regulation, Research, Health, and the Environment: The Glyphosate-Based Herbicides Case in Canada.

Despite discourse advocating pesticide reduction, there has been an exponential increase in pesticide use worldwide in the agricultural sector over the last 30 years. Glyphosate-Based Herbicides (GBHs) are the most widely used pesticides on the planet as well as in Canada, where a total of almost 470 million kilograms of declared "active" ingredient glyphosate was sold between 2007 and 2018. GBHs accounted for 58% of pesticides used in the agriculture sector in Canada in 2017. While the independent scientific literature on the harmful health and environmental impacts of pesticides such as GBHs is overwhelming, Canada has only banned 32 "active" pesticide ingredients out of 531 banned in 168 countries, and reapproved GBHs in 2017 until 2032. This article, based on interdisciplinary and intersectoral research, will analyze how as a result of the scientific and regulatory captures of relevant Canadian agencies by the pesticide industry, the Canadian regulation and scientific assessment of pesticides are deficient and lagging behind other countries, using the GBH case as a basis for analysis. It will show how, by embracing industry narratives and biased evidence, by being receptive to industry demands, and by opaque decision making and lack of transparency, Health Canada's Pest Management Regulatory Agency (PMRA) promotes commercial interests over the imperatives of public health and environmental protection.

Impact of Early Tracheostomy Versus Late or No Tracheostomy in Nonneurologically Injured Adult Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: The optimal timing of tracheostomy in nonneurologically injured mechanically ventilated critically ill adult patients is uncertain. We conducted a systematic review of randomized controlled trials to evaluate the effect of early versus late tracheostomy or prolonged intubation in this population. DATA SOURCES: We searched MEDLINE, Embase, CENTRAL, CINAHL, and Web of science databases for randomized controlled trials comparing early tracheostomy (<10 d of intubation) with late tracheostomy or prolonged intubation in adults. DATA SELECTION: We selected trials comparing early tracheostomy (defined as being performed less than 10 d after intubation) with late tracheostomy (performed on or after the 10th day of intubation) or prolonged intubation and no tracheostomy in nonneurologically injured patients. The primary outcome was overall mortality. Secondary outcomes included ventilator-associated pneumonia, duration of mechanical ventilation, ICU, and hospital length of stay. DATA EXTRACTION: Two reviewers screened citations, extracted data, assessed the risk of bias, and classification of Grading of Recommendations, Assessment, Development, and Evaluation independently. DATA SYNTHESIS: Our search strategy yielded 8,275 citations, from which nine trials (n = 2,457) were included. We did not observe an effect on the overall mortality of early tracheostomy compared with late tracheostomy or prolonged intubation (risk ratio, 0.91, 95% CI, 0.82-1.01; I2 = 18%). Our results were consistent in all subgroup analyses. No differences were observed in ICU and hospital length of stay, duration of mechanical ventilation, incidence of ventilator-acquired pneumonia, and complications. Our trial sequential analysis showed that our primary analysis on mortality was likely underpowered. CONCLUSION: In our systematic review, we observed that early tracheostomy, as compared with late tracheostomy or prolonged intubation, was not associated with a reduction in overall mortality. However, we cannot exclude a clinically relevant reduction in mortality considering the level of certainty of the evidence. A well-designed trial is needed to answer this important clinical question.

Academic dependency: the influence of the prevailing international biomedical research agenda on Argentina's CONICET.

Background: The prevailing health and biomedical sciences (HBMS) research agenda, not only determined by leading academic institutions but also by large pharmaceutical companies, has been shown to prioritize the exploration of novel pharmacological interventions over the study of the socio-environmental factors influencing illness onset and progression. The aim of this investigation is to quantitatively explore whether and to what extent the prevailing international HBMS research agenda and the key actors setting this agenda influence research in non-core countries. Methods: We used the Web of Science database and the CorText platform to proxy the HBMS research agenda of a prestigious research institution from Latin America: Argentina's National Research Council (CONICET). We conducted a bibliometric and lexical analysis of 16,309 HBMS academic articles whereby CONICET was among the authors' affiliations. The content of CONICET's agenda was represented through co-occurrence network maps of the most frequent concatenation of terms found in titles, keywords, and abstracts. We compared our findings with previous reports on the international HBMS research agenda. Results: In line with the results previously reported for the prevailing international agenda, we found that terms linked to molecular biology and cancer research hegemonize CONICET's HBMS research agenda, whereas terms connecting HBMS research with socio-environmental cues are marginal. However, we also found differences with the international agenda: CONICET's HBMS agenda shows a marginal presence of terms linked to translational medicine, while terms associated with categories such as pathogens, plant research, agrobiotechnology, and food industry are more represented than in the prevailing agenda. Conclusions: CONICET's HBMS research agenda shares topics, priorities, and methodologies with the prevailing HBMS international research agenda. However, CONICET's HBMS research agenda is internally heterogeneous, appearing to be mostly driven by a combination of elements that not only reflect academic dependency (the adoption of the prevailing research agenda by non-core research institutions) but also local economic determinants associated with Argentina's place in the international division of labor as an exporter of primary goods.

Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

Economic Evaluation of In-Hospital Clinical Practices in Acute Injury Care: A Systematic Review.

OBJECTIVES: Underuse of high-value clinical practices and overuse of low-value practices are major sources of inefficiencies in modern healthcare systems. To achieve value-based care, guidelines and recommendations should target both underuse and overuse and be supported by evidence from economic evaluations. We aimed to conduct a systematic review of the economic value of in-hospital clinical practices in acute injury care to advance knowledge on value-based care in this patient population. METHODS: Pairs of independent reviewers systematically searched MEDLINE, Embase, Web of Science, and Cochrane Central Register for full economic evaluations of in-hospital clinical practices in acute trauma care published from 2009 to 2019 (last updated on June 17, 2020). Results were converted into incremental net monetary benefit and were summarized with forest plots. The protocol was registered with PROSPERO (CRD42020164494). RESULTS: Of 33 910 unique citations, 75 studies met our inclusion criteria. We identified 62 cost-utility, 8 cost-effectiveness, and 5 cost-minimization studies. Values of incremental net monetary benefit ranged from international dollars -467 000 to international dollars 194 000. Of 114 clinical interventions evaluated (vs comparators), 56 were cost-effective. We identified 15 cost-effective interventions in emergency medicine, 6 in critical care medicine, and 35 in orthopedic medicine. A total of 58 studies were classified as high quality and 17 as moderate quality. From studies with a high level of evidence (randomized controlled trials), 4 interventions were clearly dominant and 8 were dominated. CONCLUSIONS: This research advances knowledge on value-based care for injury admissions. Results suggest that almost half of clinical interventions in acute injury care that have been studied may not be cost-effective.

Pain Management Strategies After Orthopaedic Trauma: A Mixed-Methods Study with a View to Optimizing Practices.

PURPOSE: To examine 1) pain management strategies within the care trajectory of orthopaedic trauma patients and patients' perception of their effectiveness, 2) adverse effects (AEs) associated with pharmacological treatments, particularly opioids and cannabis, and 3) patients' perceptions of strategies that should be applied after an orthopaedic trauma and support that they should obtain from health professionals for their use. PATIENTS AND METHODS: This study was conducted with orthopaedic trauma patients in a level 1 trauma center. A convergent mixed-methods design was used. Data on pain experience, pain management strategies used and AEs were collected with self-administered questionnaires at hospital discharge (T1) and at 3 months after injury (T2). Patients' preferences about the pain management strategies used, the required support and AEs were further examined through semi-structured individual interviews at the same time measures. Descriptive statistics and thematic analyses were performed. RESULTS: Seventy-one patients were recruited and 30 individual interviews were undertaken. Pharmacological pain management strategies used at T1 and T2 were mainly opioids (95.8%; 20.8%) and acetaminophen (91.5%; 37.5%). The most frequently applied non-pharmacological strategies were sleep (95.6%) and physical positioning (89.7%) at T1 and massage (46.3%) and relaxation (32.5%) at T2. Findings from quantitative and qualitative analyses highlighted that non-pharmacological strategies, such as comfort, massage, distraction, and physical therapy, were perceived as the most effective by participants. Most common AEs related to opioids were dry mouth (78.8%) and fatigue (66.1%) at T1 and insomnia (30.0%) and fatigue (20.0%) at T2. Dry mouth (28.6%) and drowsiness (14.3%) were the most reported AEs by patients using recreational cannabis. An important need for information at hospital discharge and for a personalized follow-up was identified by participants during interviews. CONCLUSION: Despite its AEs, we found that opioids are still the leading pain management strategy after an orthopaedic trauma and that more efforts are needed to implement non-pharmacological strategies. Cannabis was taken for recreational purposes but patients also used it for pain relief. Support from health professionals is needed to promote the adequate use of these strategies.

Correction: Whose shoulders is health research standing on? Determining the key actors and contents of the prevailing biomedical research agenda.

[This corrects the article DOI: 10.1371/journal.pone.0249661.].

Low-value injury admissions in an integrated Canadian trauma system: A multicentre cohort study.

BACKGROUND: Injury represents 260 000 hospitalisations and $27 billion in healthcare costs each year in Canada. Evidence suggests that there is significant variation in the prevalence of hospital admissions among emergency department presentations between countries and providers, but we lack data specific to injury admissions. We aimed to estimate the prevalence of potentially low-value injury admissions following injury in a Canadian provincial trauma system, identify diagnostic groups contributing most to low-value admissions and assess inter-hospital variation. METHODS: We conducted a retrospective multicentre cohort study based on all injury admissions in the Québec trauma system (2013-2018). Using literature and expert consultation, we developed criteria to identify potentially low-value injury admissions. We used a multilevel logistic regression model to evaluate inter-hospital variation in the prevalence of low-value injury admissions with intraclass correlation coefficients (ICC). We stratified our analyses by age (1-15; 16-64; 65-74; 75+ years). RESULTS: The prevalence of low-value injury admissions was 16% (n = 19 163) among all patients, 26% (2136) in children, 11% (4695) in young adults and 19% (12 345) in older adults. Diagnostic groups contributing most to low-value admissions were mild traumatic brain injury in children (48% of low-value paediatric injury admissions; n = 922), superficial injuries (14%, n = 660) or minor spinal injuries (14%, n = 634) in adults aged 16-64 and superficial injuries in adults aged 65+ (22%, n = 2771). We observed strong inter-hospital variation in the prevalence of low-value injury admissions (ICC = 37%). CONCLUSION: One out of six hospital admissions following injury may be of low value. Children with mild traumatic brain injury and adults with superficial injuries could be good targets for future research efforts seeking to reduce healthcare services overuse. Inter-hospital variation indicates there may be an opportunity to reduce low-value injury admissions with appropriate interventions targeting modifications in care processes.