Clinical pharmacology facing the real-world setting: Pharmacovigilance, pharmacoepidemiology and the economic evaluation of drugs.

Traditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too.

Lack of essential information in spontaneous reports of adverse drug reactions in Catalonia-a restraint to the potentiality for signal detection.

PURPOSE: The aim of this study is to analyze the quality of the information contained in the adverse drug reactions (ADR) reports and to describe the magnitude and characteristics of the lacking information. METHODS: All reports of serious ADR received by the Catalan Center of Pharmacovigilance in 2014 were analyzed using the VigiGrade and a more clinical and qualitative approach. RESULTS: Up to 824 reports describing serious ADR were included in the study; of them, 503 (61.0%) were sent by health care professionals (HPs) and the remaining 321 (39.0%) came from pharmaceutical companies (PhC). More than 80% of missing variables such as 'onset date' or 'time-to-onset' of the ADR were from PhCs reports. 'Onset of treatment date' was not filled in 28 (22.2%) of the reports including an 'additional monitoring' medicine, and 'end of treatment' date was not completed in 53 of those reports (42.1%). In summary, 39% of the reports involving a black triangle medicine sent by PhCs lacked some essential information such as the onset date of treatment. CONCLUSIONS: More than one third of the reports coming from manufacturers did not include information that is considered a limiting factor to evaluate any causal relationship, and can be an issue for the detection of safety signals. To take advantage of this huge amount of potentially important information that is almost useless at present, data mining tools and new algorithms should be developed and tested with the aim of finding formulas to deal with a huge amount of low quality data without losing it, nor generating a number of false associations.

Effectiveness of nirsevimab immunoprophylaxis against respiratory syncytial virus-related outcomes in hospital and primary care settings: a retrospective cohort study in infants in Catalonia (Spain).

BACKGROUND: In Catalonia, infants under 6 months old were eligible to receive nirsevimab, a novel monoclonal antibody against respiratory syncytial virus (RSV). We aimed to analyse nirsevimab's effectiveness across primary and hospital care outcomes. METHODS: Retrospective cohort study from 1 October 2023 to 31 January 2024, including all infants born between April and September 2023. We established two cohorts based on nirsevimab administration (immunised and non-immunised). We followed individuals until the earliest moment of an outcome-RSV infection, primary care attended bronchiolitis and pneumonia, hospital emergency visits due to bronchiolitis, hospital admission or intensive care unit (ICU) admission due to RSV bronchiolitis-death or the end of the study. We used the Kaplan-Meier estimator and fitted Cox regression models using a calendar time scale to estimate HRs and their 95% CIs. RESULTS: Among 26 525 infants, a dose of nirsevimab led to an adjusted HR for hospital admission due to RSV bronchiolitis of 0.124 (95% CI: 0.086 to 0.179) and an adjusted HR for ICU admission of 0.099 (95% CI: 0.041 to 0.237). Additionally, the adjusted HRs observed for emergency visits were 0.446 (95% CI: 0.385 to 0.516) and 0.393 (95% CI: 0.203 to 0.758) for viral pneumonia, 0.519 (95% CI: 0.467 to 0.576) for bronchiolitis attended in primary care and 0.311 (95% CI: 0.200 to 0.483) for RSV infection. CONCLUSION: We demonstrated nirsevimab's effectiveness with reductions of 87.6% and 90.1% in hospital and ICU admissions, respectively. These findings offer crucial guidance for public health authorities in implementing RSV immunisation campaigns.

Association of musculoskeletal complaints and gliptin use: review of spontaneous reports.

PURPOSE: Gliptins are new oral antidiabetic drugs that increase insulin levels through dipeptidyl peptidase-4 inhibition. Recently, the association of serious musculoskeletal (MSk) adverse effects with the gliptin use has been suggested. The aim is to describe and analyze the characteristics of spontaneous reports related to these adverse effects and gliptin use. METHODS: All spontaneous reports with MSk disorders associated with gliptins gathered in the Spanish pharmacovigilance database until May 2012 were described and analyzed using a case/non-case method. RESULTS: Gliptins were reported as the suspected drug in 332 cases: 208 involved sitagliptin, 115 vildagliptin, and nine saxagliptin. In 34 patients (10.2% of total reports with gliptins), MSk reactions were described (22 women [64.7%] and 12 men [35.3%]). Their mean age was 65.1 years; 41.2% were younger than 65 years. Only seven cases were serious, but the gliptin had to be withdrawn in 22 patients because of intolerance and/or persistence of MSk discomfort, and patients recovered after its discontinuation. A positive re-challenge was observed in two cases. In seven cases, the patients were on previous chronic treatment with statins, and began to present MSk complaints shortly after starting a gliptin. The reporting odds ratio (ROR) for myalgia and arthralgia were strongly associated with gliptin use (ROR 1.96 [95% CI 1.12-3.43], p < 0.05 and ROR 2.69 [95% CI 1.38-5.24], p < 0.05, respectively). CONCLUSIONS: Musculoskeletal disorders are adverse reactions strongly associated with gliptins that, despite not being serious, may impair the treatment adherence in patients with type 2 diabetes. Future observational studies could confirm these findings.

Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Detection and Prevention of Medication Errors by the Network of Sentinel Pharmacies in a Southern European Region.

A medication error (ME) is a drug-related problem that has been recognized as a common and serious threat to patient safety. The aim of this study was to detect and analyze ME reports occurring throughout the therapeutic process through the community's pharmacies in order to improve the efficacy and safety of medications and contribute to the prevention of future MEs. This was a three-year descriptive, observational, and prospective study to detect and analyze the different MEs reported by the Catalan sentinel pharmacies network (Catalan SePhaNet). In total, 1394 notifications of MEs were reported (an incidence rate of 737.34 cases/100,000 inhabitants). MEs were detected more frequently in primary care centers. Most of the MEs reported were caused by an incorrect, incomplete, illegible, or verbal medical prescription (41.3%). Of the global notifications detected, 71.9% did not reach the patient (categories A and B). The drugs most frequently implicated in the reported ME cases were beta-lactam antibiotics. In 6.0% of the cases, the ME caused injury to the patient (categories E and F). In 72.0% of the global notifications, a pharmacist's intervention avoided the ME. The importance of a community pharmacy and the role of a pharmacist were demonstrated in aspects related to patient and drug safety.

Safety of Drugs Used during the First Wave of COVID-19: A Hospital-Registry-Based Study.

The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.

Adverse Reactions to Drugs of Special Interest in a Pediatric Oncohematology Service.

Introduction: Drugs used in oncological diseases are frequently related to adverse drug reactions (ADR). Few studies have analyzed the toxicity of cancer treatments in children in real practice. Methods: An observational, longitudinal and prospective study has been carried out in an Oncohematology Service of a tertiary hospital. During 2017, patients exposed to one or more drugs of a previously agreed list were identified and followed-up for at least 6 months each. Characteristics of ADR, incidence, causality and possible preventability, have been evaluated. Results: 72 patients have been treated with at least one study drug, and 159 ADR episodes involving at least one of these drugs have been identified, with a total of 293 ADR. Most episodes required hospital admission (35.2%) or happened during the hospital stay (33%), and 91.2% were severe. Blood disorders were the most frequent ADR (96; 32.8%), related to thioguanine (42) and pegaspargase (39) mainly, followed by infections (86; 29.4%) related to thioguanine (32), pegaspargase (27), Erwinia asparaginase (14) and rituximab (13). Two ADR were unknown. Most ADR were dose-dependent or expectable (>90%). The global incidence of ADR was 3.1/100 days at risk (95% CI 2.7-3.5), with 3.5 ADR/100 days at risk with pegaspargase (95% CI 2.9-4.2), 1.2/100 days at risk with rituximab (95% CI 0.8-1.8) and 11.6/100 days at risk with thioguanine (95% CI 9.4-14.2). Controversial additional measures of prevention, other than those already used, were identified. Conclusion: ADR are frequent in pediatric oncohematological patients, mainly blood disorders and infectious diseases. Findings regarding incidence and preventability may be useful to compare data between different centers and to evaluate new possibilities for action or prevention.

Effect of an intervention on the features of adverse drug reactions spontaneously reported in a hospital.

OBJECTIVES: A continuous intervention based on healthcare management agreements was associated in our hospital with an increase in the absolute number of spontaneous reporting of adverse drug reactions (ADRs), and also with an increase in the number of reports of serious or unexpected ADRs and ADRs associated with new drugs. The objective was to analyse the effect of this intervention on the features of ADRs spontaneously reported in a hospital, the drugs involved and the number of signals identified. METHODS: A longitudinal study with two periods, the 1st period without intervention from 1998 to 2002 and the 2nd period with intervention from 2003 to 2005, was carried out in a tertiary teaching hospital. Changes between the two periods with regard to the following variables were analysed: the patients' characteristics, such as gender and age; the reported ADRs, and the medical assistance required; the suspected drugs involved in the ADRs; the main signals identified. RESULTS: Gender and age distribution of patients described in the spontaneous reports were no different in the two periods. During the second period, spontaneously reported cases requiring hospital admission and those occurring in hospital increased (236 from 2 in the first period and 277 from 99 in the first period respectively) and cases from outpatient hospital consultations began to be reported (13.9% of reports). The spontaneous reporting on all kinds of ADRs and drugs increased during the second period. Cutaneous reactions were the most frequently spontaneously reported ADRs in both periods followed by cardiovascular and neurological reactions in the first period, and haematological and gastrointestinal reactions in the second one. However, during the second period the higher increase was for endocrinological, urinary and hepatic reactions. Systemic antibiotics, anti-thrombotics and cardiac therapy drugs were the most common therapeutic subgroups reported to be suspected drugs in both periods, but in the second period the proportion of immunostimulants, beta blocking agents, immunosuppressants and psychoanaleptics increased. No signals were recognised during the first period; however, two signals and one additional safety concern were identified during the second. CONCLUSION: An intervention based on healthcare management agreements, was associated with an important increase in spontaneous reporting of ADRs by hospital physicians and also with a change in terms of the type of ADRs identified affecting different organs or systems, and the therapeutic groups of drugs involved. Future studies should analyse the effect of different types of intervention on the spontaneous reporting of ADRs in hospitals.

An intervention to improve spontaneous adverse drug reaction reporting by hospital physicians: a time series analysis in Spain.

BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) in hospitals is scarce and several obstacles to such reporting have been identified previously. OBJECTIVE: To assess the effectiveness of a multifaceted intervention based on healthcare management agreements for improving spontaneous reporting of ADRs by physicians in a hospital setting. METHODS: In 2003, the spontaneous reporting of ADRs was included as one of the objectives of hospital physicians at the Vall d'Hebron Hospital, Barcelona, Spain, within the context of management agreements between clinical services and hospital managers. A continuous intervention related to these management agreements, including periodic educational meetings and economic incentives, was then initiated. We carried out an ecological time series analysis and assessed the change in the total number of spontaneous reports of ADRs, and the number of serious ADRs, unexpected ADRs, and ADRs associated with new drugs between a period previous to the intervention (from 1998 to 2002) and the period during the intervention (from 2003 to 2005). A time series analysis with ARIMA (Auto-Regressive Integrated Moving Average) models was performed. RESULTS: The median number of reported ADRs per year increased from 40 (range 23-55) in the first period to 224 (range 98-248) in the second period. In the first period, the monthly number of reported ADRs was stable (3.47 per month; 95% CI 1.90, 5.03), but in the second period the number increased progressively (increase of 0.74 per month; 95% CI 0.62, 0.86). In the second period, the proportion of reported serious ADRs increased nearly 2-fold (63.1% vs 32.5% in the first period). The absolute number of previously unknown or poorly known ADRs increased 4-fold in the second period (54 vs 13 in the first period). There was also an increase in the absolute number of suspected pharmacological exposures to new drugs (97 vs 28) and in the number of different new drugs suspected of causing ADRs (50 vs 19). CONCLUSION: A continuous intervention based on healthcare management agreements with economic incentives and educational activities is associated with a quantitative and qualitative improvement of spontaneous reporting of ADRs by hospital physicians.

Dronedarone and renal impairment: evaluation of Spanish postmarketing reports and review of literature.

BACKGROUND: Renal impairment associated with dronedarone use is hardly known. Our aim is to describe the characteristics of spontaneous reports involving renal adverse reactions with use of dronedarone. METHODS: In the Spanish Pharmacovigilance database, reports with renal reactions and dronedarone until May 2014 were retrieved and analyzed. Also, a review of case reports of renal failure and dronedarone was conducted in MEDLINE. RESULTS: Dronedarone was found as a suspected drug in 192 reports, 10 (5.2%) of these reports described renal reactions. Renal reactions appeared until 3 months after the onset of dronedarone treatment. In 5 out of 10 cases, dronedarone was withdrawn and the patient recovered. The Reporting Odds Ratio was 2.88 [95% CI 1.52 - 5.46; p < 0.05]. Additionally, eight cases were found in the medical literature. In five of them, the patient outcome was described as recovered. One patient had to undergo hemodialysis for the treatment of their renal impairment. CONCLUSIONS: The effect of dronedarone on the renal function is supported by limited information; therefore, the cases from spontaneous reporting system and those from the medical literature could give relevant additional information. Our analysis shows a potential relationship between dronedarone use and renal impairment. Further studies are needed to confirm these findings.

A prospective multicenter study of the effect of patient education on acceptability of generic prescribing in general practice.

The purpose of the study was to assess patients' acceptability of the substitution of brand-name drugs for generic drugs in the primary health care prescribing practices for chronic conditions. A prospective randomised multicentre study was conducted over a 12-month period in which patients taking medications for chronic disorders received an educational intervention on generic drugs at the time they attended different general practices in the city of Barcelona (Spain) for repeat prescribing. Twenty-seven public primary care centres were randomised to the intervention group (eight centres) or the control group (19 centres). Of 4620 patients in the intervention group that received verbal information and handout materials on advantages and disadvantages of generic equivalents and brand-name drugs, 98.9% of them agreed to receive a generic formulation. The primary care centre and the class of drug were associated with statistically significant differences in the percentage of acceptance of generic drugs. In the overall population, generic prescribing in the intervention practices increased to 5.9 as compared with 2.8% in controls. In summary, individual educational intervention in patients with repeat prescribing resulted in a high rate of generic acceptability. The intervention might stimulate the practitioner's motivation, behaviour and knowledge of generic forms.

[First spontaneous reports of adverse reactions to the new selective COX-2 non-steroidal anti-inflammatory drugs]. / Primeras notificaciones espontáneas de sospechas de reacciones adversas a los nuevos antiinflamatorios selectivos sobre la ciclooxigenasa-2.

BACKGROUND: [corrected] The new selective cyclooxygenase 2 non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with a lower incidence of adverse gastrointestinal effects. MATERIAL AND METHOD: The first Yellow Cards received at the Catalan Centre of Pharmacovigilance reporting adverse effects of rofecoxib and celecoxib were reviewed and compared to those attributed to non-selective NSAIDs. RESULTS: Most frequent adverse effects of rofecoxib were gastrointestinal and cardiovascular; those of celecoxib were mostly cutaneous and gastrointestinal; and those of non-selective NSAIDs were gastrointestinal and neuropsychiatric. CONCLUSIONS: Rofecoxib and celecoxib are not devoid of gastrointestinal toxicity; they may also induce cardiovascular adverse effects.

Educational sessions in pharmacovigilance: What do the doctors think?

BACKGROUND: The aim of this study was to determine physicians' opinion regarding pharmacovigilance feedback sessions. A survey was conducted in a teaching hospital, and the physicians who attended the sessions were invited to participate by filling out a structured questionnaire. All sessions included a review of adverse drug reactions identified at the hospital and information on pharmacovigilance issues (news on warnings released by regulatory agencies or drug toxicity problems identified by recently published studies in medical journals). The survey questions were related to the interest, satisfaction, and belief in the utility of the sessions. A Likert scale (0-10 points) was used to assess physicians' opinions. FINDINGS: A total of 159 physicians attended the sessions and 115 (72.3%) participated in the survey. The mean (SD) age was 38.9 (12.1) years, and 72 (62.6%) were men. The mean (SD) scores of interest, satisfaction with the information provided, and belief in the utility of these sessions were 7.52 (1.61), 7.58 (1.46), and 8.05 (1.38) respectively. Significant differences were observed among physicians according to medical category and speciality in terms of interest, satisfaction, and belief in the utility of those sessions. CONCLUSIONS: Educational activities for physicians, such as feedback sessions, can be integrated into the pharmacovigilance activities. Doctors who attend the sessions are interested in and satisfied with the information provided and consider the sessions to be useful. Additional studies on the development and effectiveness of educational activities in pharmacovigilance are necessary.