Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Original Form in Combination With Methotrexate in Patients With Rheumatoid Arthritis: A Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

BACKGROUND: Enerceptan (EtaBS) has been developed as a proposed biosimilar of etanercept. METHODS: This randomized, multicenter, evaluator-blinded, noninferiority study conducted in Argentina included adults with active, moderate, and severe rheumatoid arthritis with inadequate response to methotrexate. Subjects were randomly assigned to 32 weeks treatment with EtaBS (n = 99) or etanercept (n = 51) at a weekly 50-mg dose administered subcutaneously. Patients were categorized according to prior use of biologic disease-modifying antirheumatic drugs and concomitant use of steroids. The primary efficacy endpoint was ACR20 response rate at week 32. Safety, immunogenicity, and steady-state concentration of both drugs were evaluated. The noninferiority margin for ACR20 was estimated at 12%. RESULTS: In the per-protocol population, 85 subjects (92.4%) treated with EtaBS and 44 subjects (93.6%) treated with etanercept achieved ACR20 (difference, -1.2%; 95% confidence interval, -10.1% to 7.6%). Frequent adverse drug reactions occurred in 34.3% and 38% of subjects treated with EtaBS and etanercept, respectively. The most common reaction was upper respiratory tract infection. Six and 3 serious adverse events occurred in 4 and 3 subjects treated with EtaBS and etanercept, respectively. Injection site reactions occurred in 67.7% and 66.0% of subjects treated with EtaBS and etanercept, respectively. Two subjects treated with EtaBS and 1 subject treated with etanercept developed antibodies by week 32. CONCLUSIONS: Efficacy outcomes for EtaBS were noninferior to original etanercept in patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate. Safety and immunogenicity results were comparable between the two. This study is a major step toward improving access to biologics in Latin America.

Breaking the unvirtuous cycle: barriers and opportunities for research and development in Paraguay. A case study.

Introduction: Medical research and development (R&D) is an undoubtedly relevant activity to drive innovation, improve healthcare policies and bring patients treatment opportunities for common and rare diseases. Equity and inclusion are matters of concern in research. High-income countries' research teams are more likely to have more impactful publications, grant funding, and clinical trials than middle or low-income countries. Low budget allocations to R&D and existing gaps in regulatory frameworks are some obstacles to growth. This unvirtuous cycle results in scarce advances in common endemic diseases and the underrepresentation of specific populations in innovative therapeutics research. Materials and methods: We conducted a policy review and qualitative research to determine the principal characteristics of basic and clinical medical research in Paraguay, as well as barriers and facilitators to improve innovative R&D strategies in this country. To this aim, we examined published articles from 2005 to 2020, the organizational structure of national research agencies, the current regulation framework, and the composition and experience of local research groups and ethical review boards (ERBs). In addition, we performed semi-structured interviews to evaluate perceptions and expectations from different stakeholders, including investigators, ERBs members, sponsor associates, and Regulatory Agency executive staff. Results: In 2018, Paraguay ranked 10th out of 12 South American countries in total number of publications and cumulative h-index score. Total Gross Domestic Product (GDP) allocation for R&D was 0.15%, ranking eighth out of 12 in the region. In 2021, the number of trials registered on ClinicalTrials.gov was 52, with only 16 ongoing recruiting studies at that time.Some of the main barriers identified included low incentives for academic careers and lack of experience in pharmaceutical research. An emergent necessity to develop a straight- forward normative framework was detected. Main facilitators included the development of two research initiative programs (PRONII and PROCIENCIA) from CONACYT (National Council of Science and Technology) which were associated with higher budget allocation and total number of publications in the 2011 to 2017 period. A total of six stakeholders participated in the semi-structured surveys. Interviewees highlighted the necessity of a centralized policy to promote R&D, which incorporates investigators and ERBs training, the development of standardized procedures, and the dissemination of research activities. Sponsor associates underlined that real-world evidence may represent a distinctive opportunity to enhance local research. Conclusion: Coordinated efforts are needed to break the unvirtuous cycle. There is an increasing interest in enhancing health research in Paraguay, materialized in the creation of specific programs that encourage the collaborative work of healthcare providers, basic scientists, and private investors. Nonetheless, a comprehensive approach is needed also to strengthen regulatory agencies and attract external sponsorship. While modern and currently popular topics, including artificial intelligence, real-world data, and translational research may represent key opportunities to seek investment, special policies should be adopted to prioritize research on the determinants of health in the Paraguayan population.

Biosimilar Versus Originator Pegfilgrastim for Preventing Chemotherapy-Induced Neutropenia: A Phase III Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

PURPOSE: This study evaluated the efficacy, safety, and immunogenicity of biosimilar pegfilgrastim (PegFilBS) and originator pegfilgrastim (PegFilOR) in patients with stage 2-4 breast cancer. METHODS: This phase III randomized, multicenter, evaluator-blinded, noninferiority study recruited women with stage 2-4 breast cancer in Argentina who were scheduled to receive chemotherapy. Stratification was based on the breast cancer stage. The primary end point was the duration of severe neutropenia (DSN, noninferiority margin: 1 day) in the first chemotherapy cycle. Secondary end points assessed were incidence of severe neutropenia, grade 3 neutropenia, febrile neutropenia, infections, postchemotherapy hospitalization and duration, and the incidence of adverse drug reactions (ADRs). RESULTS: A total of 120 patients were randomly assigned to receive PegFilBS (58 patients) or PegFilOR (62 patients). Severe neutropenia occurred in 52 of 283 cycles (18.4%) for 27 patients who received PegFilBS and in 48 of 297 cycles (16.2%) for 20 patients who received PegFilOR (P = .48). During the first cycle, severe neutropenia occurred in 16 patients who received PegFilBS (DSN: 0.78 ± 1.53 days) and in 11 patients who received PegFilOR (DSN: 0.53 ± 1.25 days; 95% CI, -0.26 to 0.76 days). In the intention-to-treat analysis, the mean DSN values were 0.90 ± 1.79 days for the PegFilBS group and 0.50 ± 1.21 for the PegFilOR group (95% CI, -0.15 to 0.95 days). No significant differences were observed for the secondary efficacy end points. Three patients experienced seven ADRs in the PegFilBS group while 10 patients experienced 31 ADRs in the PegFilOR group. The most common ADR was myalgia. CONCLUSION: Relative to PegFilOR, PegFilBS provided noninferior efficacy outcomes in Argentinian women with stage 2-4 breast cancer who were treated using myelosuppressive chemotherapy.

Efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) vs. Gonal-f® in women undergoing ovarian stimulation for IVF: A randomized, multicenter, evaluator-blinded, non-inferiority study.

OBJECTIVE: We compared the efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) with Gonal-f® in women undergoing ovarian stimulation for in-vitro fertilization. METHODS: This randomized (1:1), multicenter, assessor-blinded, non-inferiority, parallel-group, controlled study conducted at four infertility clinics in Argentina included infertile normogonadotropic women with ages below 39 years, with menstrual cycles of 25/35 days and a body mass index of 18-32 kg/m2 undergoing assisted reproductive technology therapy. During a 5-day fixed-dose phase, the women received 225 IU/day of Folitime® (n=49) or Gonal-f® (n=44), followed by a dose-adaptation phase up to a maximum of 450 IU/day. The non-inferiority margin for oocyte retrieval was estimated at -4 oocytes (one-sided test). Immunogenicity was investigated on days 9 and 84, following the start of treatment. RESULTS: The mean number of oocytes retrieved was 12.6 (SD 7.4) in the Folitime® group and 13.4 (SD 6.9) in the Gonal-f® group (per protocol analysis, 95% confidence interval = -3.82; 2.33), within the non-inferiority margin. Pregnancy rate at week 10 was 24.4% among subjects treated with Folitime® and 19.5% for subjects treated with Gonal-f®. One serious adverse drug reaction-late mild ovarian hyper stimulation syndrome and deep venous thrombosis in the left deep jugular vein-occurred in a subject treated with Folitime®. None of the subjects developed antibodies against the study drugs. There were no unexpected safety findings. CONCLUSIONS: Folitime® is non-inferior to Gonal-f®, with no differences in the safety profile and has been approved as a biosimilar in Argentina.

[Deregulation and equity: the Obras Sociales reconversion process in Argentina]. / Desregulación y equidad: el proceso de reconversión de Obras Sociales en Argentina.

The health care services managed by trade unions and known as "Obras Sociales" form the groundwork for Argentina's Social Security and Health system. However, far from taking an equitable approach, these institutions highlight the country's prevailing income disparities, which in turn lead to major differences in access to care. The main focus of this study was the reformulation of social security health policies within the framework of deregulation from 1998 to 2000, analyzing the effects on availability of health care services from an equity perspective. The methodology used two related analytical levels: (1) a macro level viewing the process from the various players' strategies and (2) a micro level featuring the changes within a well-known trade union social security organization during its reconversion process, emphasizing its institutional scope and the opinions of its membership. The results thus pointed to the slow implementation of reforms initiated by the public sector, hindered by constant negotiations among the main corporate actors seeking to serve their particular interests, along with increased inequity and fragmentation due to the limited opening of free choice by members.

[Declaration of Helsinki: its vicissitudes during the last five years]. / Declaración de Helsinki. Sus vicisitudes en los últimos cinco años.

The Declaration of Helsinki is one of the major ethical guidelines for conducting clinical research. Along its existence it has been modified on diverse occasions, the latest one in October 2000. The objective of this article is to carry out a revision of the discussions that were taken up at this latest modification and the debates raised since its promulgation which still continue, fundamentally in relation to the use of placebo in pharmacological clinical investigation. This includes a revision of the most outstanding articles and of the opinions of the participants in the discussions that have been published in the last five years. The scientists' arguments in favor or against the use of placebo are pointed out. We consider that it is difficult to find simple answers to the questions raised by the use of placebo in clinical trials both in developed countries and in countries under development and that the Declaration of Helsinki continues to constitute a guide of ethical ideal which all those involved in clinical research should try to take into consideration.

Adherencia al tratamiento en pacientes con artritis reumatoidea / Adherence to treatment in patients with rheumatoid arthritis

Objetivo: Este estudio se propone evaluar el cumplimiento del tratamiento farmacológico en pacientes con AR e identificar los factores que pueden afectar al mismo. Materiales y métodos: Estudio observacional, analítico, transversal. Se realizaron encuestas a 176 pacientes de la base de datos, seleccionados al azar de un centro privado especializado en Reumatología ubicado en el conurbano sur de la provincia de Buenos Aires (Instituto Médico CER - Quilmes). Entre septiembre de 2015 y julio de 2016 fueron realizadas de manera telefónica por voluntarios no médicos de la Fundación Articular entrenados a tal fin. Se utilizaron los cuestionarios BAM, CQR19 y se indagó la percepción del paciente sobre su grado de adhesión al tratamiento dividiéndolo en dos grupos: cumplimiento total o cumplimiento parcial/nulo. Se recabaron datos sociodemográficos, estado de enfermedad, tratamiento, comorbilidades y hábitos. Se utilizaron las siguientes pruebas estadísticas: ANOVA de un factor para evaluar diferencias en niveles medios de CQR19 y variables cualitativas; prueba de Brown-Forsythe para determinar asociación entre CRQ y diversas variables, correlación no paramétrica Rho de Spearman entre CQR19 y variables cuantitativas y regresión logística para explicar adherencia al tratamiento (CQR19 agrupada). Los datos fueron analizados usando el programa SPSS (versión 19.0). Resultados: El 85,8% eran mujeres y la edad promedio fue de 55,1 años. El 51,1% de los pacientes considera que su salud es buena con relación a la AR y el 40,9% considera que es regular. El tratamiento más frecuente fue MTX oral (79%). La monoterapia fue la modalidad terapéutica más referida (79,5%) y el tiempo medio de tratamiento es de 4,4 años. La actitud de los pacientes hacia los medicamentos mostró acuerdo en los 5 ítems que corresponden a la dimensión necesidad del BAM. El nivel de acuerdo-desacuerdo resultó más heterogéneo en los ítems de la dimensión preocupación. CQR19 mostró alto nivel de acuerdo en la mayor parte de los ítems positivos y alto nivel de desacuerdo en la mayor parte de los ítems negativos. Las únicas variables que se asociaron a mayor CQR fueron la presencia de comorbilidades (Brown-Forsythe=7,960; p=0,005) y medicación concomitante (Brown-Forsythe=7,529; p=0,007). También se encontró asociación significativa entre CRQ19 y tabaquismo (F=0,019; p=0,981). Se observó correlación significativa entre CQR y BAM Específico-Necesidad (Rho=0,379; p <0,001) y entre CQR y BAM Específico-Preocupación (Rho=-0,188; p=0,012). Se observó mayor adherencia cuando el paciente siente la necesidad de cumplir con la medicación (O.R.=1,342; p=0,012) y cuando menos preocupado está por la misma (O.R.=0,870; p=0,047). Detectamos menor cumplimiento del tratamiento en pacientes casados o que viven en pareja (Chi²=7,448; p=0,024) y con mayor nivel educativo (Chi²=6,313; p=0,043). Cuando se evalúa el cumplimiento de la medicación prescrita por indagación directa a los pacientes, el nivel de cumplimiento es más elevado. Conclusión: Se trata de una población con nivel moderado de adherencia. Mayor conciencia de necesidad de medicación y menor nivel de preocupación acerca de la misma generan mayor adherencia. Los pacientes sobreestiman el cumplimiento de la medicación cuando se los interroga de manera directa por lo cual es mandatorio utilizar otro método de evaluación. El mayor conocimiento de la adherencia de los pacientes con AR nos permitirá desarrollar herramientas que mejoren este aspecto a largo plazo.

Objective: This study aims to evaluate the compliance of pharmacological treatment in patients with RA and identify the factors that may affect it. Materials and methods: Observational, analytical and cross-sectional study. Surveys were conducted on 176 randomly selected patients from a private center specialized in Rheumatology located in the southern suburbs of the province of Buenos Aires (CER Medical Institute - Quilmes), between September 2015 and July 2016, by telephone by trained non-medical volunteers of the Articular Foundation. The BAM, CQR19 questionnaires were used and the patient's perception of their degree of adherence to the treatment was investigated, dividing it into two groups: total compliance or partial/no compliance. Sociodemographic data, disease status, treatment, comorbidities and habits were collected. The following statistical tests were used: one-way ANOVA to evaluate differences in mean levels of CQR19 and qualitative variables; Brown-Forsythe test to determine the association between CRQ and various variables, non-parametric Spearman's Rho correlation between CQR19 and quantitative variables and logistic regression to explain adherence to treatment (CQR19 grouped). The data was analyzed using the SPSS program (version 19.0). Results: 85.8% were women and the average age was 55.1 years. 51.1% of patients consider that their health is good in relation to RA and 40.9% consider it to be fair. The most frequent treatment was oral MTX (79%). Monotherapy was the most referred therapeutic modality (79.5%) and the mean treatment time is 4.4 years. The attitude of the patients towards the medicines showed agreement in the 5 items that correspond to the dimension of necessity of the BAM. The level of agreement-disagreement was more heterogeneous in the items of the concern dimension. CQR19 showed a high level of agreement in most of the positive items and a high level of disagreement in most of the negative items. The only variables that were associated with higher CQR were the presence of comorbidities (Brown-Forsythe=7.960, p=0.005) and concomitant medication (Brown-Forsythe=7.529, p=0.007). There was also a significant association between CRQ19 and smoking (F=0.019, p=0.981). Significant correlation was observed between CQR and BAM Specific-Necessity (Rho=0.379, p <0.001) and between CQR and BAM Specific-Concern (Rho=-0.188; p=0.012). Greater adherence was observed when the patient felt the need to comply with the medication (O.R.=1.342, p=0.012) and when least concerned about it (O.R.=0.870, p=0.047). We detected less compliance with treatment in married patients or those living with a partner (Chi²=7.448, p=0.024) and with a higher educational level (Chi²=6.313, p=0.043). When the compliance of the prescribed medication is evaluated by direct inquiry to the patients, the level of compliance is higher. Conclusion: It is a population with a moderate level of adherence. Greater awareness of the need for medication and a lower level of concern about it generate greater adherence. Patients overestimate medication compliance when they are interrogated directly, which is why it is mandatory to use another evaluation method. The greater knowledge of the adherence of patients with RA will allow us to develop tools that improve this aspect in the long term.

Desregulación y equidad: el proceso de reconversión de Obras Sociales en Argentina / Deregulation and equity: the Obras Sociales reconversion process in Argentina

The health care services managed by trade unions and known as "Obras Sociales" form the groundwork for Argentina's Social Security and Health system. However, far from taking an equitable approach, these institutions highlight the country's prevailing income disparities, which in turn lead to major differences in access to care. The main focus of this study was the reformulation of social security health policies within the framework of deregulation from 1998 to 2000, analyzing the effects on availability of health care services from an equity perspective. The methodology used two related analytical levels: (1) a macro level viewing the process from the various players' strategies and (2) a micro level featuring the changes within a well-known trade union social security organization during its reconversion process, emphasizing its institutional scope and the opinions of its membership. The results thus pointed to the slow implementation of reforms initiated by the public sector, hindered by constant negotiations among the main corporate actors seeking to serve their particular interests, along with increased inequity and fragmentation due to the limited opening of free choice by members.

Declaracion de Helsinki: sus vicisitudes en los ultimos cinco años / Declaration of Helsinki: its vicissitudes during the last five years

The Declaration of Helsinki is one of the major ethical guidelines for conducting clinical research. Along its existence it has been modified on diverse occasions, the latest one in October 2000. The objective of this article is to carry out a revision of the discussions that were taken up at this latest modification and the debates raised since its promulgation which still continue, fundamentally in relation to the use of placebo in pharmacological clinical investigation. This includes a revision of the most outstanding articles and of the opinions of the participants in the discussions that have been published in the last five years. The scientists' arguments in favor or against the use of placebo are pointed out. We consider that it is difficult to find simple answers to the questions raised by the use of placebo in clinical trials both in developed countries and in countries under development and that the Declaration of Helsinki continues to constitute a guide of ethical ideal which all those involved in clinical research should try to take into consideration

Cobertura de prácticas de prevención del cáncer cervical uterino y mamario: análisis de una población asintomática en el Partido de La Matanza / Practical cover of prevention of the cervical and breast cancer: analysis of an asymptomatic population in the La Matanza district

El presente trabajo informa la cobertura del Pap, examen clínico mamario y autoexamen mamario en una población asintomática autoseleccionada para participar de un Programa de Detección del Cáncer y evaluar la concordancia entre los tests mencionados. Método: Se realizaron encuestas individuales a cada mujer atendida. Se utilizó el índice de Kappa para evaluar la concordancia. Resultados: 69,3 por ciento de las mujeres se realizaron un Pap en los últimos tres años y 37,1 por ciento el examen clínico mamario en el mismo lapso. 13,2 por ciento de las mujeres nunca se hizo un Pap y en 44,1 por ciento nunca fueron examinadas sus mamas. La concordancia fue significativa (p<0,0001). Conocen el autoexamen mamario 87,9 por ciento de las mujeres, pero lo realizan el 62,4 por ciento. Discusión y Conclusiones: Este es el primer informe en nuestro país que describe la cobertura de estas prácticas de detección. La realización del examen físico mamario es muy baja. De las mujeres que se hacen un Pap el 44 por ciento no recibe un examen físico mamario, sugiriendo una falla profesional o del sistema de salud

Conocimientos y prácticas de detección del cáncer génito mamario resultados de una encuesta poblacional / Knowledge and detection behaviors of genital and breast cancer: a population survey

El presente trabajo describe conocimientos y prácticas de la población femenina en relación a la detección del cáncer génito-mamario. Metodología: se realizó una encuesta poblacional domiciliaria entre las mujeres de 30 a 64 años del Partido de San Fernando entre octubre y noviembre de 1995. Se consideraron factores demográficos, antecedentes relevantes y conocimientos y prácticas preventivas, especialmente del cáncer cervical uterino y mamario. Se realizó un análisis bivariado para determinar la relación entre los distintos factores y las prácticas realizadas

Factores que influyen en la práctica de la citología exfoliativa cervical y el examen clínico mamario: evaluación de una población en el partido de La Matanza / Factors when influen in the practic of the cervical exfoliative cytology and breast clinical examination: evaluation of a population in the La Matanza distict

El presente trabajo informa acerca de diversos factores que pudieran afectar la práctica de la citología exfoliativa cervical (Pap) y el examen clínico mamario (EF) por parte de una población absolutamente asintomática que concurrió voluntariamente a un Programa de Detección de Cáncer de Mama. Método: Se realizaron encuestas individuales a 779 mujeres utilizó el Odd Ratio para cada variable estudiada y luego se incluyeron las variables significativas en un análisis de regresión logística. Resultados: La edad (30-49: OR 3,2; 50-60: OR 3,8) el nivel educacional (primario completo: OR 2,0) la paridad (1-3 hijos: OR 4,3; >3 hijos: OR 2,6) y el antecedente familiar de cáncer excepto mama predicen la posibilidad de haberse realizado el Pap alguna vez. La edad (30-49: OR 2,4; 50-69: OR 2,5), el nivel educacional (secundario: OR 2,0; terciario: OR 3,0), el antecedente familiar de cáncer excepto mama (con antecedentes: OR 1,6) el antecedente familiar de cáncer de mama (con antecedentes: OR 3,0), de patología mamaria clínica (con antecedentes: OR 2,8) y de patología mamaria quirúrgica (con antecedentes OR 3,8) influyen en la probabilidad de haberse sometido a un EF. Discusión y Conclusiones: Las mujeres de menos de 30 años, de menor nivel educacional y sin hijos se encuentran más desprotegidas en cuanto a la detección de cáncer genitomamario