Evaluation of factors associated with recruitment rates in early phase clinical trials based on the European Clinical Trials Register data.

Effective participant recruitment is a critical challenge in clinical trials. Inadequate enrollment of participants can precipitate delays, escalated costs, and compromise scientific integrity. Despite its relevance, particularly during the early phases, it persists as an obstacle in the field of clinical research. The primary aim of this study was to analyze the recruitment rates of early-phase clinical trials and evaluate their potential associations with key trial characteristics. Using a descriptive and statistical analysis, a research study was conducted based on the early-phase trials registered at the European Clinical Trials Register (EU-CTR), spanning the timeframe from January 2017 to December 2021. Among the 194 trials examined, we found median recruitment rates of 68%. A more detailed exploration revealed a greater level of success in terms of recruitment achievement in pediatric trials when compared to trials involving adults, non-oncologic trials, or those also developed in non-European countries. It is important to underscore that only 69 trials out of the total managed to conclude recruitment, with the most prevalent reason for premature cessation being the presence of efficacy and safety issues or sponsor's strategy. This number can be greatly improved. Despite certain disparities observed in the information within EU-CTR, we have successfully determined the recruitment rates of the studies and established associations with some of the clinical trial characteristics analyzed. Owing to the inherent constraints of this study, further research is warranted to gain a comprehensive understanding of the intricate interplay between trial characteristics and their impact on recruitment rates in early-phase studies.

Immune-Mediated Organ-Specific Reactions to COVID-19 Vaccines: A Retrospective Descriptive Study.

Severe acute respiratory syndrome coronavirus 2 caused the global COVID-19 pandemic and public health crisis, and it led to the rapid development of COVID-19 vaccines, which can cause rare and typically mild hypersensitivity reactions (HRs). Delayed HRs to COVID-19 vaccines have been reported, and the excipients polyethylene glycol (PEG)2000 and polysorbate 80 (P80) are the suspected culprits. Skin patch tests do not help in diagnosing delayed reactions. We aimed to perform lymphocyte transformation tests (LTT) with PEG2000 and P80 in 23 patients with suspected delayed HRs. Neurological reactions (n = 10) and myopericarditis reactions (n = 6) were the most frequent complications. Seventy-eight percent (18/23) of the study patients were admitted to a hospital ward, and the median time to discharge was 5.5 (IQR, 3-8) days. Some 73.9% of the patients returned to baseline condition after 25 (IQR, 3-80) days. LTT was positive in 8/23 patients (5/10 neurological reactions, 2/4 hepatitis reactions and 1/2 rheumatologic reactions). All myopericarditis cases had a negative LTT. These preliminary results indicate that LTT with PEGs and polysorbates is a useful tool for identifying excipients as causal agents in HRs to COVID-19 vaccines and can play an important role in risk stratification in patients with HRs.

Anti-cancer drug combinations approved by US FDA from 2011 to 2021: main design features of clinical trials and role of pharmacokinetics.

During the last decade, the treatment for many cancer indications has evolved due to intensive clinical research into anti-tumor agents' combination. In most instances, new combination treatments consist of an add-on to the standard of care (SOC), which then demonstrate a substantial gain in efficacy and no detrimental effect in tolerability. In the era of targeted therapies, for which maximum tolerated dose (MTD)-based dosing strategies are no longer applicable, early stage studies exploring new combinations are often conducted in the population of interest, expediting the collection of preliminary safety data, to be promptly expanded to collect preliminary efficacy data. Nevertheless, rule-based dose-finding studies are still a prevailing approach for early stage cancer, especially for chemotherapy (CT)-containing combinations. Pharmacokinetic (PK) assessments play a key role throughout the clinical development of drug combinations, informing potential PK interactions. But most importantly, they allow the development of innovative exposure-response (E-R) models aimed at exploring the contribution of each agent to the overall effect of the combination therapy. This review identifies 81 new drug combinations approved by the United States Food and Drug Administration (FDA) for hemato-oncology during the 2011-2021 period and summarizes the main design features of clinical trials and the role of PK assessments.

Acute Poisoning Readmissions to an Emergency Department of a Tertiary Hospital: Evaluation through an Active Toxicovigilance Program.

The aim of this study is to investigate hospital readmissions during 1 year after acute poisoning cases (APC), analyze the temporal behavior of early readmissions (ER) (in the month after the index episode) and predict possible ER. A descriptive analysis of the patients with APC assisted between 2011 and 2016 in the Emergency Department of Hospital La Paz is presented, and various methods of inferential statistics were applied and confirmed by Bayesian analysis in order to evaluate factors associated with total and early readmissions. Out of the 4693 cases of APC included, 968 (20.6%) presented, at least one readmission and 476 (10.1%) of them were ER. The mean age of APC with readmission was 41 years (12.7 SD), 78.9% had previous psychiatric pathology and 44.7% had a clinical history of alcohol addiction. Accidental poisoning has been a protective factor for readmission (OR 0.50; 0.26-0.96). Type of toxin ("drug of abuse" OR 8.88; 1.17-67.25), history of addiction (OR 1.93; 1.18-3.10) and psychiatric history (OR 3.30; 2.53-4.30) are risk factors for readmissions during the first year. Women showed three or more readmissions in a year. The results of the study allow for identification of the predictors for the different numbers of readmissions in the year after the index APC, as well as for ERs.

Characterisation of Drug-Induced Liver Injury in Patients with COVID-19 Detected by a Proactive Pharmacovigilance Program from Laboratory Signals.

Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

Incidence of Suspected Serious Adverse Drug Reactions in Corona Virus Disease-19 Patients Detected by a Pharmacovigilance Program by Laboratory Signals in a Tertiary Hospital in Spain: Cautionary Data.

BACKGROUND: From March to April 2020, Spain was the center of the SARS-CoV-2 pandemic, particularly Madrid with approximately 30% of the cases in Spain. The aim of this study is to report the suspected serious adverse drug reactions (SADRs) in COVID-19 patients vs. non-COVID-19 patients detected by the prospective pharmacovigilance program based on automatic laboratory signals (ALSs) in the hospital (PPLSH) during that period. We also compared the results with the suspected SADRs detected during the same period for 2019. METHODS: All ALSs that reflected potential SADRs including neutropenia, pancytopenia, thrombocytopenia, anemia, eosinophilia, leukocytes in cerebrospinal fluid, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis, and hyponatremia were prospectively monitored in hospitalized patients during the study periods. We analyzed the incidence and the distribution of causative drugs for the COVID-19 patients. RESULTS: The incidence rate of SADRs detected in the COVID-19 patients was 760.63 (95% CI 707.89-816.01) per 10,000 patients, 4.75-fold higher than the SADR rate for non-COVID-19 patients (160.15 per 10,000 patients, 95% CI 137.09-186.80), and 5.84-fold higher than the SADR rate detected for the same period in 2019 (130.19 per 10,000 patients, 95% CI 109.53-154.36). The most frequently related drugs were tocilizumab (59.84%), dexketoprofen (13.93%), azithromycin (8.43%), lopinavir-ritonavir (7.35%), dexamethasone (7.62%), and chloroquine/hydroxychloroquine (6.91%). CONCLUSIONS: The incidence rate of SADRs detected by the PPSLH in patients with COVID-19 was 4.75-fold higher than that of the non-COVID-19 patients. Caution is recommended when using medications for COVID-19 patients, especially drugs that are hepatotoxic, myotoxic, and those that induce thromboembolic events.