Evolution of Pharmacological Treatments and Associated Costs for Multiple Myeloma in the Public Healthcare System of Catalonia: A Retrospective Observational Study.

(1) Background: Our understanding of and treatment for multiple myeloma (MM) has advanced significantly, and new pharmacological treatments have promising benefits but high price tags. This study analyzes prescription patterns and pharmaceutical expenditure for MM treatments in Catalonia's public healthcare system over eight years. (2) Methods: A retrospective observational study examined MM treatment data from 2015 to 2022 in Catalonia, using healthcare registries from the Catalan Health Service to collect information on patients, medicines used, and treatment costs. (3) Results: A total of 4556 MM patients received treatment, with a rising trend in the number of treated patients each year from 902 in 2015 to 1899 in 2022. The mean age was 68.9 years, and patients were almost evenly distributed by gender (51.5% male). Most patients were treated with bortezomib (3338 patients), lenalidomide (2952), and/or daratumumab (1093). Most drugs showed increased utilization annually, most significantly for lenalidomide and daratumumab. The total pharmacological treatment cost throughout the entire study period was EUR 321,811,249, with lenalidomide leading with the highest total cost (EUR 157,236,784), and daratumumab exhibiting the highest increase in annual expenditure. (5) Conclusions: The study reveals a progressive increase in the number of MM patients treated and rising pharmaceutical costs. Lenalidomide and daratumumab incurred the highest costs. The findings highlight MM treatment's economic impact and the need to monitor prescription patterns and expenditures to optimize healthcare resources and decision making. Understanding these trends can guide resource allocation effectively.

The challenges of access to innovative medicines with limited evidence in the European Union.

The European Medicines Agency (EMA) fosters access to innovative medicines through accelerated procedures and flexibility in the authorization requirements for diseases with unmet medical needs, such as many rare diseases as well as oncological diseases. However, the resulting increase of medicines being marketed with conditional authorizations and in exceptional circumstances has lead to higher clinical uncertainty about their efficacy and safety than when the standard authorizations are applied. This uncertainty has significant implications for clinical practice and the negotiation of pricing and reimbursement, particularly as high prices are based on assumptions of high value, supported by regulatory prioritization. The burden of clinical development is often shifted towards public healthcare systems, resulting in increased spending budgets and opportunity costs. Effective management of uncertainty, through appropriate testing and evaluation, and fair reflection of costs and risks in prices, is crucial. However, it is important not to sacrifice essential elements of evidence-based healthcare for the sake of access to new treatments. Balancing sensitive and rational access to new treatments, ensuring their safety, efficacy, and affordability to healthcare systems requires thoughtful decision-making. Ultimately, a responsible approach to timely access to innovative medicines that balances the needs of patients with healthcare systems' concerns is necessary. This approach emphasizes the importance of evidence-based decision-making and fair pricing and reimbursement.

Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union.

Several advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1-3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22-118). To date, ATMPs' approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs.

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States.

BACKGROUND AIMS: Regulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions. METHODS: A retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions. RESULTS: In the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU. CONCLUSIONS: The current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.

Corrigendum: Regulatory Framework for Advanced Therapy Medicinal Products in Europe and United States.

[This corrects the article DOI: 10.3389/fphar.2019.00921.].

Regulatory Framework for Advanced Therapy Medicinal Products in Europe and United States.

Advanced therapy medicinal products (ATMPs) are a fast-growing field of innovative therapies. The European Union (EU) and the United States (US) are fostering their development. For both regions, ATMPs fall under the regulatory framework of biological products, which determines the legal basis for their development. Sub-classifications of advanced therapies are different between regions, while in EU, there are four major groups, i.e., gene therapy, somatic cell therapy, tissue-engineered therapies, and combined advanced therapies; in US, the sub-classification covers two major groups of products, i.e., gene therapy and cellular therapy. The inclusion criteria that define a gene therapy are equivalent in both regions, and the exclusion criteria are directly related to the indications of the product. In the EU, there is a clear differentiation between cell- and tissue-based products regarding their classification as advanced therapies or coverage by other legal frameworks, whereas in US, there is a broader classification about whether or not these products can be categorized as biologic products. Both in EU and in US, in order to classify a cell- or a tissue-based product as an advanced therapy, it must be ensured that the processing of the cells implies a manipulation that alters their biological characteristics, although the term of manipulation in US differentiates between structural and non-structural cells and tissues. The regulatory terminology used to define ATMPs and their sub-classification reveals some differences between EU and US.

Use of α2-Adrenergic Agonists to Improve Surgical Field Visibility in Endoscopy Sinus Surgery: A Systematic Review of Randomised Controlled Trials.

PURPOSE: We assessed the evidence for the use of α2-adrenergic agonists (A2AAs) in bleeding control and field quality in endoscopic sinus surgery. METHODS: We systematically reviewed randomized clinical trials (RCTs) assessing A2AAs in endoscopic sinus surgery. Abstracts were reviewed by 2 investigators for eligibility, and selected articles were fully reviewed. Data on study design, population, A2AA drug and control groups, bleeding and surgical field quality outcomes, and adverse effects were extracted and synthesized. FINDINGS: A total of 13 RCTs that included 896 individuals (7 double-blind trials, 5 single-blind trials, and 1 open-label trial) were selected that assessed the efficacy of clonidine (6 RCTs, 407 patients), dexmedetomidine (6 RCT, 423 patients), or both (1 RCT, 66 patients). Clonidine was compared with placebo (3 RCTs), midazolam (1 RCT), and remifentanil (2 RCTs). Dexmedetomidine was compared with esmolol (2 RCTs), remifentanil (2 RCTs), nitroglycerin and esmolol (1 RCT), and magnesium sulfate (1 RCT). Clonidine and dexmedetomidine were compared in 1 RCT. Clonidine reduced the proportion of individuals with an impaired surgical field by 23% vs placebo (number needed to treat = 4). Clonidine was better than midazolam and remifentanil in 2 trials, and dexmedetomidine was better than magnesium sulfate and esmolol in 2 trials but was not superior to esmolol, remifentanil, or nitroglycerin in 4 trials. Dexmedetomidine produced significantly better differences in bleeding outcomes versus clonidine. Adverse events were infrequent and mainly caused by hypotension or bradycardia. IMPLICATIONS: RCTs consistently report that A2AAs reduce bleeding and improve surgical field quality during endoscopic sinus surgery. Adverse event reporting was often omitted in RCTs. Well-designed RCTs with appropriate sample sizes are desirable to identify the best A2AAs and confirm their potential effects on clinical outcomes.

Have We Improved Pain Control in Cancer Patients? A Multicenter Study of Ambulatory and Hospitalized Cancer Patients.

BACKGROUND: Pain in cancer patients is recognized as a major health problem, yet few studies of both inpatient and outpatient populations have been carried out. OBJECTIVE: The study objective was to assess the frequency, type, and characteristics of pain in adult cancer patients, including both inpatients and outpatients. METHODS: This cross-sectional study involved 1064 adult cancer patients (437 outpatients and 627 inpatients) from 44 hospitals and/or long-term-care centers in Catalonia, Spain. Cancer patients suffering from pain of any etiology for ≥2 weeks and/or under analgesic treatment ≥2 weeks were enrolled. Demographic and pain data were collected. The Spanish version of the Brief Pain Inventory was used to assess pain. RESULTS: Pain frequency was 55.3%. Pain was less frequent in outpatients than inpatients (41.6% versus 64.7%; p<0.001), although median pain duration was longer in outpatients (20 versus 6 weeks; p<0.001). Pain was assessable in 333 patients, and intensity was similar in both out- and inpatients; however, outpatients reported less improvement, less pain interference with daily life, and less pain related to the cancer per se. In both groups, patients with multiple myeloma (73%), breast (65%), and lung cancer (61%) were most likely to report pain. CONCLUSIONS: Pain in cancer patients, both ambulatory and hospitalized, remains a challenge for health care professionals, health administrators, and stakeholders. Our study reveals the high level of pain and distress that cancer patients continue to suffer, a problem that is particularly notable in outpatients due to the intensity and duration of the pain.

Fármacos que inhiben el factor de necrosis tumoral α y embarazo / Anti-tumor necrosis factor-α medications and pregnancy

No disponible

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.

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.

Antimicrobianos y embarazo / Antimicrobials and pregnancy

Los cambios fisiológicos que ocurren durante el embarazo condicionan cambios farmacocinéticos que pueden alterar la efectividad de los antimicrobianos y, además, hay que tener en cuenta el posible riesgo teratogénico y la toxicidad de estos medicamentos sobre el embrión y el feto. En general, las mujeres embarazadas son excluidas de los ensayos clínicos y hay escasa información farmacocinética respecto al uso y la dosificación adecuados de los antimicrobianos en las mujeres embarazadas. Además, la mayoría de antimicrobianos cruzan la barrera hematoplacentaria, pero los datos relacionados con su potencial teratogénico y su toxicidad fetal y neonatal también son limitados y tienen una fiabilibad variable. En este artículo se revisan las evidencias disponibles y de mayor relevancia clínica relacionadas con la farmacología de diferentes antibacterianos, antifúngicos, antivirales y antiparasitarios en las mujeres embarazadas, con un énfasis especial en los datos de toxicidad fetal (AU)

The physiologic changes that occur during pregnancy result in pharmacokinetic changes that can alter the effectiveness of antimicrobial agents. The possible risk of teratogenic and toxic effects of antimicrobials on the fetus is an additional cause of concern. In general, pregnant women are excluded from clinical trials and there is little pharmacokinetic information on the use and proper dosing of antimicrobials in this population. Although most antimicrobials can cross the placental blood barrier, data on the potential teratogenic effects, and fetal and neonatal toxicity caused by antimicrobials are also limited and of varying reliability. This article reviews the available evidence with the greatest clinical relevance regarding the pharmacology of different antibiotic, antifungal, antiviral, and antiparasitic agents in pregnancy, with particular focus on data related to fetal toxicity (AU)

[Antimicrobials and pregnancy]. / Antimicrobianos y embarazo.

The physiologic changes that occur during pregnancy result in pharmacokinetic changes that can alter the effectiveness of antimicrobial agents. The possible risk of teratogenic and toxic effects of antimicrobials on the fetus is an additional cause of concern. In general, pregnant women are excluded from clinical trials and there is little pharmacokinetic information on the use and proper dosing of antimicrobials in this population. Although most antimicrobials can cross the placental blood barrier, data on the potential teratogenic effects, and fetal and neonatal toxicity caused by antimicrobials are also limited and of varying reliability. This article reviews the available evidence with the greatest clinical relevance regarding the pharmacology of different antibiotic, antifungal, antiviral, and antiparasitic agents in pregnancy, with particular focus on data related to fetal toxicity.

[Assessment of factors associated with patients' comprehension of treatment at the start of antiretroviral therapy]. / Evaluación de factores asociados a la comprensión del tratamiento en pacientes que inician la terapia antirretroviral.

OBJECTIVE: The aim of this study was to evaluate factors associated with patients' comprehension of antiretroviral therapy (ART). METHOD: Cross-sectional analysis in which patients at 2 HIV/AIDS public referral centers (Belo Horizonte, Brazil) were interviewed after initiating ART. Information was recorded on variables related to the patient's characteristics, the treatment prescribed, and the healthcare professional involved. A score indicating the patients' level of comprehension regarding the medications prescribed was obtained using a latent trait model estimated by the item response theory. RESULTS: A total of 406 patients were interviewed. Mean (SD) age was 35 (10) years, 227 were men (56%), 302 of Afro-American ethnicity (77%), and 213 had <8 years of education (53%). The regression model determined that 52.25% of the variability of comprehension was explained by the individual's characteristics. Variables associated (P<0.05) with poorest understanding about ART were lower education (<8 years), lack of knowledge about treatment duration and clinical severity, inadequate information provided by physicians, inability to understand pharmaceutical information, daily number of tablets, and the ART regimen prescribed. CONCLUSION: Comprehension of information about the ART regimen prescribed varies considerably between individuals. Nonetheless, several factors were found to be associated with the level of understanding: characteristics of the patient (education, clinical severity), characteristics of treatment (daily number of tablets, ART regimen prescribed), and contribution of healthcare professionals (information from physicians and pharmacists). Strategies to reinforce information about ART should be a priority for patients with a low level of understanding.

Evaluación de factores asociados a la comprensión del tratamiento en pacientes que inician la terapia antirretroviral / Assessment of factors associated with patients¿ comprehension of treatment at the start of antiretroviral therapy

Objetivo: el objetivo del estudio fue evaluar los factores asociados con el nivel de comprensión de la terapia antirretroviral (TARV). Método: estudio transversal en el que los pacientes de 2 servicios públicos de referencia para el tratamiento del virus de la inmunodeficiencia humana (VIH)/sida (Belo Horizonte, Brasil) fueron entrevistados después de iniciar la TARV. Se recogió información acerca de las variables relacionadas con las características del paciente, del tratamiento prescrito y de los profesionales sanitarios. La puntuación de la comprensión de los medicamentos prescritos se estimó mediante un modelo de trazo latente por la teoría de respuesta al ítem. Resultados: se entrevistaron 406 pacientes con una edad media (desviación estándar) de 35 (10) años, de los que 227 fueron varones (56%), 302 de etnia afroamericana (77%) y 213 con una escolaridad <8 años (53%). El modelo de regresión mostró que un 52,25% de la variabilidad de la comprensión era explicado por el individuo. Las variables asociadas con un menor nivel de comprensión (p<0,05) fueron: menor escolaridad (<8 años); desconocimiento de la duración de la TARV; gravedad clínica; información médica inadecuada; incapacidad de entender la información farmacéutica; número diario de comprimidos, y esquema de TARV prescrito. Conclusión: hay una alta variabilidad individual en la comprensión de la información acerca de la TARV. Sin embargo, hay factores relacionados con las características del paciente (escolaridad y gravedad clínica), del tratamiento (dosis diaria y esquema TARV) y de los profesionales sanitarios (información del médico y del farmacéutico) asociados con el grado de comprensión. Se deberían priorizar las estrategias de refuerzo de la información acerca de la TARV en los pacientes con un bajo nivel de comprensión (AU)

Objective: The aim of this study was to evaluate factors associated with patients¿ comprehension of antiretroviral therapy (ART). Method: Cross-sectional analysis in which patients at 2 HIV/AIDS public referral centers (Belo Horizonte, Brazil) were interviewed after initiating ART. Information was recorded on variables related to the patient's characteristics, the treatment prescribed, and the healthcare professional involved. A score indicating the patients¿ level of comprehension regarding the medications prescribed was obtained using a latent trait model estimated by the item response theory. Results: A total of 406 patients were interviewed. Mean (SD) age was 35 (10) years, 227 were men (56%), 302 of Afro-American ethnicity (77%), and 213 had <8 years of education (53%). The regression model determined that 52.25% of the variability of comprehension was explained by the individual's characteristics. Variables associated (P<0.05) with poorest understanding about ART were lower education (<8 years), lack of knowledge about treatment duration and clinical severity, inadequate information provided by physicians, inability to understand pharmaceutical information, daily number of tablets, and the ART regimen prescribed. Conclusion: Comprehension of information about the ART regimen prescribed varies considerably between individuals. Nonetheless, several factors were found to be associated with the level of understanding: characteristics of the patient (education, clinical severity), characteristics of treatment (daily number of tablets, ART regimen prescribed), and contribution of healthcare professionals (information from physicians and pharmacists). Strategies to reinforce information about ART should be a priority for patients with a low level of understanding (AU)