Oswaldo L. Bracco

Merck & Co., Inc., Rahway, NJ, USA (United States)

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Marcia J. Kayath

Novartis (United States)

David H. Henry

Pennsylvania Hospital

Mercêdes Jurema Oliveira Alves

Brazilian Medical Association

Sandra Inês Ruschel

Hospital Estadual Mário Covas

Juliana Oliveira

Vifor Pharma (Switzerland)

Allan Lipton

Pennsylvania State University

Paul J. Kostenuik

University of Michigan–Ann Arbor

Catherine Van Poznak

University of Michigan–Ann Arbor

Alison Stopeck

University of Arizona

Toni Ibrahim

Istituto Ortopedico Rizzoli

Cooperative Institutions

Merck & Co., Inc., Rahway, NJ, USA (United States)

Universidade Federal de São Paulo

Memorial Sloan Kettering Cancer Center

Eli Lilly (United States)

Universidade de São Paulo

Dana-Farber Cancer Institute

Harvard University

Fundação de Apoio à Universidade Federal de São Paulo

Cornell University

Brigham and Women's Hospital

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Regulator‐Requested Non‐Interventional Postauthorization Safety and Effectiveness Studies for Oncology Drugs: A Systematic Review

Clinical Pharmacology & Therapeutics (2021)

Xiao Zhang Lei Chen Oswaldo L. Bracco Soko Setoguchi Wei Zhou

There has been a growing number of oncology drug approvals. Non-interventional postauthorization safety/effectives studies (PASSs/PAESs) aim to provide real-world evidence on the safety/effectiveness of oncology drugs postapproval. To understand the current landscape, a comprehensive search as of March 1, 2021, was conducted in major register/databases. We found that requested studies increased from 1 in 2006-2010 to 47 in 2016-2020. Of 78 total studies identified, 50 focused on safety/risk assessment (64.1%), 6 on effectiveness (7.7%), 3 on drug utilization (3.8%), 1 on disease epidemiology (1.3%), and 18 on effectiveness of additional risk minimization measures (23.1%). For safety/risk assessment studies, 58.9% focused on nonspecific end points (e.g., frequency of adverse events). For effectiveness studies, the leading primary outcome was overall survival. Overall, safety/risk assessment studies concerning nonspecific end points for vascular endothelial growth factor (receptor) inhibitors were most requested. Regarding data sources, though a majority (71.8%) used primary data collection, a growing proportion utilized secondary data sources. Among 23 studies with information available on study design, 10 (43.5%) were single-arm cohort studies, 9 (39.1%) were cross-sectional studies, 3 (13.1%) were comparative cohort studies, and 1 (4.3%) was a nested-case-control study. In conclusion, there was an increasing number of oncology-specific non-interventional PASSs/PAESs, with a majority on safety/risk assessment. Although most utilized primary data collection, there was an increasing use of secondary real-world data sources. Few conducted comparative analyses, and most used single-arm designs. Future efforts are needed to assess how findings of these studies would impact regulatory decisions and improve knowledge of toxicity for clinical/translational development.

10.1002/cpt.2450

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Hypocalcaemia in patients with metastatic bone disease treated with denosumab

European Journal of Cancer (2015)

Jean-Jacques Body Henry G. Bone Richard H. De Boer Alison Stopeck Catherine Van Poznak

This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab.Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836).The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 μg/L [median] versus ⩽ 20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline.Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia.

Hypocalcaemia

Denosumab

Zoledronic Acid

Bone disease

10.1016/j.ejca.2015.05.016

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Regulatory benefit–risk assessment of oncology drugs: A systematic review of FDA and EMA approvals

Drug Discovery Today (2023)

Cathy Anne Pinto Zaneta Balantac Shahrul Mt‐Isa Xinyue Liu Oswaldo L. Bracco

The European Medicines Agency (EMA) and FDA have policy goals of strengthening benefit-risk (B-R) capabilities; but how this has been translating into regulatory practice is unclear. A systematic review of oncology drug approvals between 2015 and 2020 was conducted with approvals identified through review of FDA and EMA annual reports, with extraction of information on submission, clinical program and B-R assessment from publicly available review documents. Data were extracted from 236 reviews (EMA: 66 new submissions, 100 label extensions; FDA: 70 new submissions). The standard of evidence for B-R assessments seems to have diversified over time; yet, despite policy targets to extend their use, these assessments rarely include patient experience or real-world data.

Time line

Harmonization

Drug approval

10.1016/j.drudis.2023.103719

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Citations (1)

Raloxifene Action On Bone And Efficacy On Reduction Of Fracture Risk [ação Do Raloxifeno No Tecido ósseo E Sua Eficácia Na Redução Do Risco De Fraturas]

Scopus (2003)

J. F. M. Neto Marcia J. Kayath Oswaldo L. Bracco

Raloxifene

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<![CDATA[<B>Weight gain management in patients with schizophrenia during treatment with olanzapine in association with nizatidine</B>]]>

Brazilian Journal of Psychiatry (2006)

Sheila S. M. Assun��o Sandra Inês Ruschel Lucena C. R. Rosa Jo�o A. O. Campos Mercêdes Jurema Oliveira Alves

Objective: Weight gain is associated with treatment with many psychotropic agents. Nizatidine, H2 receptor antagonist, has been proposed to have weight-reducing effects. This was a 12-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of nizatidine in reducing/limiting weight gain in patients with schizophrenia who have been under treatment with olanzapine. Method: Patients receiving olanzapine (2 to 6 months) and weight gain ≥ 5% of their body weight during olanzapine treatment were randomly assigned to receive nizatidine 600 mg or placebo for up to 12 weeks. Change in psychopathology was assessed using Brief Psychiatric Rating Scale scores from baseline to endpoint. Safety was assessed using the Safety Assessed Software, assessment of glucose and lipid blood levels, and treatment-emergent adverse events. Results: Out of 54 patients enrolled in this analysis, 45 completed the protocol. The mean weight change prior randomization was 7.6 kg and 7.3 kg for those randomized to placebo and nizatidine, respectively (p = 0.828). Patients receiving placebo and nizatidine had a mean weight gain of 12.3% (0.7 kg) and 12% (1.1 kg) from baseline to endpoint, respectively (p = 0.9). Patients from both groups experienced a statistically significant decrease on the Brief Psychiatric Rating Scale mean score from baseline to endpoint. Treatment-emergent adverse events were reported by 18.5% and 25.9% on the placebo and nizatidine group, respectively. There were no statistically significant differences in glucose and lipid blood levels from baseline to endpoint and between groups. Conclusions: The concomitant use of olanzapine with nizatidine was not effective in controlling weight gain in patients who had previously gained weight during treatment with olanzapine when compared to placebo. Descriptors: Schizophrenia; Antipsychotics agents; Weight gain; Clozapine; Nizatidine

10.1590/s1516-44462006000700005

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Teriparatida (PTH[1-34]rh): uma nova perspectiva no tratamento da osteoporose

Acta Ortopédica Brasileira (2003)

Juliana H. Oliveira Oswaldo L. Bracco Marcia J. Kayath Roberto Guarniero

No momento, as medicações aprovadas para tratamento da osteoporose agem reduzindo a taxa de perda óssea e diminuindo a reabsorção óssea. A teriparatida é um fragmento recombinante sintético de 34 aminoácidos do hormônio paratireóide humano. A teriparatida se liga ao receptor de PTH da proteína G e estimula a formação e a ação dos osteoblastos, que são as células responsáveis pela formação dos ossos. Assim, a principal diferença entre o tratamento da osteoporose com teriparatida e o tratamento anti-reabsorção é que a teriparatida promove o crescimento de osso novo. Em estudos pré-clínicos, o uso intermitente de PTH foi associado com um aumento significativo da massa óssea gradeada em diversos locais. A exposição intermitente ao PTH durante 4 a 6 semanas em modelos de animais ovariectomizados leva a um aumento da espessura do osso gradeado. Há estudos clínicos que mostram que a teriparatida aumenta significativamente a densidade óssea e diminui a incidência de fraturas osteoporóticas vertebrais e não-vertebrais nas mulheres com osteoporose pós-menopáusica e têm risco alto de fratura, e aumenta a densidade óssea nos homens com osteoporose, tanto hipogonádica como idiopática. A teriparatida é dada por injeção subcutânea diária e foi associada com um mínimo de efeitos colaterais, além de não apresentar interações medicamentosas. Sendo assim, a teriparatida surge como uma abordagem completamente nova no tratamento da osteoporose, estimulando diretamente a formação do osso.

10.1590/s1413-78522003000300007

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Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients

European Journal of Cancer (2024)

Julie R. Brahmer Georgina V. Long Omid Hamid Edward B. Garon Roy S. Herbst

Background Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. Methods Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. Results Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, 7 administrations; range, 1−59). Median duration on treatment was 4.1 months (range, 0.03−40.1). AEs occurred in 96.6% of patients. Grade 3−5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3−5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13–163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. Conclusions This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Discontinuation

10.1016/j.ejca.2024.113530

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Elevada morbimortalidade e reduzida taxa de diagnóstico de osteoporose em idosos com fratura de fêmur proximal na cidade de São Paulo

Arquivos Brasileiros de Endocrinologia & Metabologia (2008)

Érika M. Fortes Maurício P. Raffaelli Oswaldo L. Bracco Edmilson Takehiro Takata Fernando Baldy dos Reis

As fraturas osteoporóticas de fêmur proximal trazem graves conseqüências quanto à morbimortalidade e à qualidade de vida, mas desconhece-se este impacto no Brasil. OBJETIVO: Conhecer a morbimortalidade decorrente deste tipo de fraturas em idosos na cidade de São Paulo. MÉTODOS: Foram incluídos todos os pacientes com mais de 60 anos internados por fraturas de fêmur proximal durante seis meses, em dois hospitais de São Paulo. Os pacientes preencheram o questionário de capacidade funcional (HAQ), tiveram seu prontuário examinado e foram reavaliados após seis meses. Utilizou-se a análise de regressão linear para determinar os fatores relacionados à capacidade funcional. RESULTADOS: Cinqüenta e seis pacientes foram incluídos no estudo (80,7 ± 7,9 anos; 80,4% mulheres). A mortalidade em seis meses foi de 23,2%. Apenas 30% retornaram plenamente às suas atividades prévias e 11,6% tornaram-se completamente dependentes. Os fatores que mais bem conseguiram prever pior capacidade funcional após a fratura foram HAQ pré-fratura, institucionalização pós-fratura e idade (r² 0,482). Somente 13,9% receberam o diagnóstico de osteoporose e 11,6% iniciaram algum tratamento. CONCLUSÕES: Os resultados do presente estudo demonstram o impacto deste tipo de fraturas sobre a mortalidade e a capacidade funcional. Entretanto, a falha médica no diagnóstico e na orientação de tratamento da osteoporose permanece elevada.

10.1590/s0004-27302008000700006

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Hormônio da paratireóide (1-34) no tratamento da osteoporose

Arquivos Brasileiros de Endocrinologia & Metabologia (2003)

Oswaldo L. Bracco Marcia J. Kayath José Gilberto H. Vieira

O hormônio da paratireóide (PTH) é produzido nas glândulas paratireóides e atua no tecido ósseo e rins, controlando a concentração sérica do cálcio e fósforo. Há muito tempo, observou-se que doses intermitentes de PTH poderiam agir anabolicamente no tecido ósseo. Vários estudos clínicos demonstram que o PTH recombinante humano (1-34) aumenta a densidade mineral óssea, promove ganho de tecido ósseo com melhora da conectividade trabecular e reduz o risco de fraturas vertebrais e extra-vertebrais em mulheres com osteoporose da pós-menopausa, mulheres com osteoporose corticóide-induzida e homens com osteoporose idiopática. A redução do risco de fraturas promovida pelo PTH (1-34) persiste após a suspensão da terapêutica, indicando seu efeito prolongado no tecido ósseo. Revisamos os dados existentes na literatura sobre o efeito anabólico do PTH (1-34) no tecido ósseo e seu uso clínico no tratamento da osteoporose.

10.1590/s0004-27302003000300014

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Custo da fratura osteoporótica de fêmur no sistema suplementar de saúde brasileiro

Arquivos Brasileiros de Endocrinologia & Metabologia (2005)

Denizar Vianna Araújo Juliana H. Oliveira Oswaldo L. Bracco

OBJETIVO: Estimar custo direto durante hospitalização para fratura osteoporótica de fêmur no sistema privado de saúde brasileiro, pela perspectiva das empresas de planos de saúde. MÉTODOS: Estudo transversal e retrospectivo sobre custos hospitalares em pacientes acima de 50 anos com fratura osteoporótica de fêmur, entre julho 2003 e junho 2004. A amostra estudada foi extraída da base de dados de processamento eletrônico das faturas de pacientes beneficiários de planos de saúde. RESULTADOS: Houve 129.611 pacientes com diagnóstico de osteoporose. A incidência de fratura osteoporótica de fêmur foi 4,99% (mulheres). A média de permanência hospitalar foi 9,21 dias (2,13 dias na UTI). O custo médio total da hospitalização foi de R$ 24.000. O maior componente de custo foi atribuído ao material médico (61%). O impacto econômico da fratura osteoporótica de fêmur foi estimado em R$ 12 milhões. CONCLUSÃO: Os custos do tratamento da fratura osteoporótica de fêmur são consideráveis no sistema privado de saúde brasileiro. Este estudo destaca a minimização de custos para empresas de planos de saúde caso a fratura osteoporótica de fêmur possa ser evitada.

10.1590/s0004-27302005000600007

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Citations (51)