Potential negative impact of reputed regulators' decisions on the approval status of new cancer drugs in Latin American countries: A descriptive analysis.

BACKGROUND: Many new cancer drugs are being approved by reputed regulatory authorities without evidence of overall survival benefit, quality of life improvement, and often based on clinical trials at high risk of bias. In recent years, most Latin American (LA) countries have reformed their marketing authorization (MA) rules to directly accept or abbreviate the approval process in case of earlier authorization by the European Medicines Agency (EMA) and the US Food and Drug Administration, mainly. This study assessed the potential impact of decisions taken by EMA regarding the approval of new cancer drugs based on no evidence of overall survival or in potentially biased clinical trials in LA countries. DESIGN: Descriptive analysis. SETTING: Publicly accessible marketing authorization databases from LA regulators, European Public Assessment Report by EMA, and previous studies accessing EMA approvals of new cancer drugs 2009-2016. MAIN OUTCOME AND MEASURES: Number of new cancer drugs approved by LA countries without evidence of overall survival (2009-2013), and without at least one clinical trial scored at low risk of bias, or with no trial supporting the marketing authorization at all (2014-2016). RESULTS: Argentina, Brazil, Chile, Colombia, Ecuador, Panama and Peru have publicly accessible and trustful MA databases and were included. Of the 17 cancer drugs approved by EMA (2009-2013) without evidence of OS benefit after a postmarketing median time of 5.4 years, 6 LA regulators approved more than 70% of them. Of the 13 drugs approved by EMA (2014-2016), either without supporting trial or with no trial at low risk of bias, Brazil approved 11, Chile 10, Peru 10, Argentina 10, Colombia 9, Ecuador 9, and Panama 8. CONCLUSIONS: LA countries keep approving new cancer drugs often based on poorly performed clinical trials measuring surrogate endpoints. EMA and other reputed regulators must be aware that their regulatory decisions might directly influence decisions regarding MA, health budgets and patient's care elsewhere.

Regulatory reliance to approve new medicinal products in Latin American and Caribbean countries / Utilización de decisiones de autoridades regulatorias de otras jurisdicciones para aprobar nuevos productos medicinales en países de América Latina y el Caribe / Uso de decisões regulatórias de outras jurisdições para aprovação de novas especialidades farmacêuticas em países da América Latina e Caribe

ABSTRACT Objective. To describe the current status of regulatory reliance in Latin America and the Caribbean (LAC) by assessing the countries' regulatory frameworks to approve new medicines, and to ascertain, for each country, which foreign regulators are considered as trusted regulatory authorities to rely on. Methods. Websites from LAC regulators were searched to identify the official regulations to approve new drugs. Data collection was carried out in December 2019 and completed in June 2020 for the Caribbean countries. Two independent teams collected information regarding direct recognition or abbreviated processes to approve new drugs and the reference (trusted) regulators defined as such by the corresponding national legislation. Results. Regulatory documents regarding marketing authorization were found in 20 LAC regulators' websites, covering 34 countries. Seven countries do not accept reliance on foreign regulators. Thirteen regulatory authorities (Argentina, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Mexico, Panama, Paraguay, Peru, Uruguay, and the unique Caribbean Regulatory System for 15 Caribbean States) explicitly accept relying on marketing authorizations issued by the European Medicines Agency, United States Food and Drug Administration, and Health Canada. Ten countries rely also on marketing authorizations from Australia, Japan, and Switzerland. Argentina, Brazil, Chile, and Mexico are reference authorities for eight LAC regulators. Conclusions. Regulatory reliance has become a common practice in the LAC region. Thirteen out of 20 regulators directly recognize or abbreviate the marketing authorization process in case of earlier approval by a regulator from another jurisdiction. The regulators most relied upon are the European Medicines Agency, United States Food and Drug Administration, and Health Canada.

RESUMEN Objetivo. Describir el estado actual de la utilización de las decisiones de autoridades regulatorias de otras jurisdicciones en América Latina y el Caribe mediante la evaluación de los marcos regulatorios nacionales para la aprobación de nuevos medicamentos y establecer los organismos regulatorios extranjeros que se consideran autoridades regulatorias confiables para cada país. Métodos. Se realizaron búsquedas en los sitios web de las autoridades regulatorias de América Latina y el Caribe para identificar las regulaciones oficiales para la aprobación de nuevos medicamentos. La recopilación de datos se llevó a cabo en diciembre del 2019 y se completó en junio del 2020 para los países del Caribe. Dos equipos independientes recopilaron información sobre el reconocimiento directo o los procedimientos abreviados para la aprobación de nuevos medicamentos y los autoridades regulatorias de referencia (confiables) así definidos en la legislación nacional correspondiente. Resultados. Se encontraron documentos regulatorios sobre la aprobación de nuevos productos en los sitios web de veinte organismos regulatorios de América Latina y el Caribe, que abarcaban 34 países. Siete países no aceptan la utilización de decisiones de autoridades regulatorias extranjeras. Trece autoridades regulatorias (Argentina, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, México, Panamá, Paraguay, Perú, República Dominicana, Uruguay y el sistema regulador único para quince Estados del Caribe) aceptan de manera explícita confiar las decisiones para aprobación de nuevos medicamentos emitidas por la Agencia Europea de Medicamentos, la Administración de Alimentos y Medicamentos de Estados Unidos y Salud Canadá. Diez países aceptan también utilizar las autorizaciones para la comercialización de Australia, Japón y Suiza. Argentina, Brasil, Chile y México son autoridades de referencia para ocho autoridades regulatorias en la región. Conclusiones. La utilización de las decisiones de autoridades regulatorias de otras jurisdicciones se han convertido en una práctica común en América Latina y el Caribe. Trece de veinte autoridades regulatorias reconocen directamente o abrevian el proceso de aprobación de nuevos medicamentos en caso de que hayan recibido previamente la aprobación por parte de un organismo regulatorio de otra jurisdicción. La Agencia Europea de Medicamentos, la Administración de Alimentos y Medicamentos de Estados Unidos y Salud Canadá son las autoridades regulatorias de otras jurisdicciones en las cuales los reguladores de América Latina y el Caribe confían más.

RESUMO Objetivo. Descrever a prática atual de uso de decisões regulatórias de outras jurisdições na América Latina e no Caribe (ALC) mediante avaliação os marcos regulatórios dos países para aprovação de novos medicamentos e verificar, para cada país, quais entidades reguladoras estrangeiras são consideradas autoridades reguladoras de confiança por cada país. Métodos. Foi realizada uma pesquisa nos sites das autoridades reguladoras da ALC para identificar as regulamentações oficiais para aprovação de novos medicamentos. A coleta de dados foi feita em dezembro de 2019 e concluída em junho de 2020 para os países do Caribe. Dois grupos independentes coletaram informações sobre o reconhecimento direto ou o procedimento abreviado para aprovação de novos medicamentos e as autoridades reguladoras de referência (de confiança) definidas como tal pela respectiva legislação nacional. Resultados. Documentos regulatórios relacionados à aprovação de novos produtos foram obtidos de 20 sites de órgãos reguladores da ALC, abrangendo 34 países. Sete países não admitem o uso de decisões regulatórias de entidades reguladoras externas. Treze autoridades reguladoras (na Argentina, Colômbia, Costa Rica, El Salvador, Equador, Guatemala, México, Panamá, Paraguai, Peru, República Dominicana, Uruguai e o Sistema Regulador do Caribe unificado para 15 Estados caribenhos) admitem explicitamente a admissibilidade de decisões regulatórias para aprovação de novos medicamentos de outras jurisdições, quais sejam: Agência Europeia de Medicamentos (EMA), Agência Reguladora de Alimentos e Medicamentos (FDA) dos EUA e Health Canada. Dez países também aceitam decisões para autorização de comercialização da Austrália, Japão e Suíça. Argentina, Brasil, Chile e México são autoridades de referência para oito agências reguladoras. Conclusões. O uso de decisões regulatórias de outras jurisdições tornou-se prática comum na América Latina e Caribe. Treze das 20 agências reguladoras reconhecem diretamente ou abreviam o procedimento de aprovação de novos medicamentos no caso de tal aprovação já haver sido concedida por uma autoridade reguladora de outra jurisdição. A EMA, a FDA e a Health Canada são as autoridades estrangeiras nas quais as agências reguladoras da América Latina e Caribe mais confiam.

Risk Factors Related to New-Onset Diabetes after Renal Transplantation in Patients of a High Complexity University Hospital in Colombia, 20 Years of Experience.

INTRODUCTION: New-onset diabetes after transplantation (NODAT) is associated with immunosuppression. Its complications can negatively influence patients' quality of life, which is why it is important to study the associated risk factors and expand the possible therapies in this particular group of patients. Materials and methods. Case-control study nested in a retrospective cohort. It included patients who received kidney transplantation at the high complexity University Hospital Fundación Valle del Lili in Cali, Colombia, between 1995 and 2014. Two controls were assigned for each case, depending on the type of donor and the date of the surgery. Information was collected from clinical records and the institutional TRENAL registry. We carried out a descriptive analysis of the selected variables and identified the risk factors with conditional logistic regression. RESULTS: 122 cases were identified to which 224 controls were assigned. The median age was 44 years (IQR: 34-55), and 54% were men. Having >50 years of age at the time of transplantation (OR: 3.18, 95% CI: 1.6-6.3, p = 0.001), body mass index >30 kg/m2 (OR: 3.6, 95% CI: 1.3-9.7, p = 0.010) and being afro-descendant (OR: 2.74, 95% CI: 1.1-6.5, p = 0.023) were identified as risk factors for the development of NODAT. Pretransplant fasting plasma glucose >100 mg/dl (OR: 2.9, 95% CI: 1.4-6.4, p = 0.005) and serum triglycerides >200 mg/dl (OR: 2.5, 95% CI: 1.4-4.4, p = 0.002) were also reported as independent risk factors. CONCLUSION: We ratify some risk factors for the development of this important disease, which include certain modifiable characteristics. Interventions aimed at changes in lifestyle could be established in a timely manner before transplant surgery.

Systematic review of anticholinergic risk scales in older adults.

BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.

Earlier decrease of FGF-23 and less hypophosphatemia in preemptive kidney transplant recipients.

BACKGROUND: Levels of fibroblast growth factor (FGF)-23, a phosphaturic hormone, increase from the early stages of CKD and are dramatically elevated in dialysis patients. Excessive FGF-23 may be involved in the hypophosphatemia and inappropriately low calcitriol levels observed after kidney transplantation (KT).This prospective observational cohort study was carried out to determine whether there are any differences in the changes in FGF-23 levels after surgery in KT recipients according to whether they were or not on dialysis before transplantation and to assess the influence of FGF-23 in the development of posttransplantation hypophosphatemia. METHODS: Consecutive KT recipients at the Hospital Clinic of Barcelona were recruited. Patients developing delayed graft function were excluded. Mineral metabolism parameters, including C-terminal fragment of FGF-23, intact parathyroid hormone, and 1,25(OH)(2)D(3), were measured in 72 KT recipients (58 on dialysis before transplantation and 14 preemptive transplant recipients) at baseline, on day 15, and at 1, 3, and 6 months after transplantation. No patients received treatment with calcimimetics, bisphosphonates, vitamin D, or phosphate supplementation during the follow-up. RESULTS: FGF-23 decreased significantly in the first month after transplantation. Baseline and FGF-23 levels within the first posttransplantation month were lower in preemptive transplant recipients than in patients on dialysis at transplantation. Serum phosphate levels were lower in dialysis patients until the third month after transplantation. Pretransplantation FGF-23 was the main predictor of posttransplantation phosphate blood levels. CONCLUSIONS: FGF-23 levels and the risk of developing posttransplantation hypophosphatemia were lower in preemptive kidney transplant recipients than in patients on dialysis before transplantation.

Successful treatment of calcific uraemic arteriolopathy with bisphosphonates.

BACKGROUND AND OBJECTIVES: Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition that almost exclusively affects patients with chronic kidney disease. Several therapies have been employed to treat this disease but with irregular results. We report a prospective case series of eight patients diagnosed with CUA in our unit between 2002 and 2010. MATERIAL AND METHOD: The series consisted of eight patients with CUA (including 4 men, 5 dialysis patients and 3 with functioning allografts) who were treated with bisphosphonates. The diagnosis was by clinical suspicion and a confirmatory biopsy. Five patients had a previous history of high calcium-phosphorus product, 6 had a history of high parathyroid hormone levels (>800pg/ml), 4 had undergone parathyroidectomy, 5 had a history of high cumulative doses of steroids, and 6 patients were under dicoumarin treatment. None of the patients were obese or had diabetes mellitus. RESULTS: In all patients, progression of skin lesions stopped between 2 to 4 weeks after starting bisphosphonate therapy, with no changes in blood levels of calcium and phosphate. Improvement in pain and lesions was faster in patients receiving intravenous ibandronate. All of these patients remained on bisphosphonate treatment for at least 6 months until the wounds healed completely. No recurrences have been observed after follow-up periods between 1 and 9 years. Renal function remained stable in transplant recipients. The treatment was well tolerated and no adverse effects were observed. CONCLUSIONS: Bisphosphonates could be a new and attractive alternative to treat CUA.