Increasing FDA-accelerated approval of single-arm trials in oncology (1992 to 2020).

OBJECTIVES: We aimed to map the characteristics of single-arm trials (SAT), report the Food and Drug Administration (FDA) transparency in presenting historical control, and to assess the confirmatory randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: This metaresearch included a review of all oncology indication approved using SAT by FDA-AA (FDA-Accelerated Approval) from 1992 to 2020. Two independent reviewers identified SAT, extracted data from FDA full medical reviews for historical controls reported and MEDLINE for searching for confirmatory RCT published. RESULTS: Of 254 FDA-AA approvals, 119 (47%) were approved for oncologic indications using SAT. Fifty-four drugs for 72 oncology indications were for leukemia, lymphoma, lung cancer, urothelial cancer, multiple myeloma, and thyroid cancer. Overall, 37 (52%) treatments were converted into regular approval. Of these, 17 (46%) were based on confirmatory RCTs using overall survival (OS) as an outcome. Five indications were withdrawn from the market. Most trials outcomes were blindly assessed by independent research committees. Median trial sample size was 105 patients (min:8 to max:532). The FDA did not fully specify historical control selection in 75% of cases. CONCLUSION: The granting of FDA-AAs based on SAT in oncology is increasing with more target drugs approved over time. Transparency in historical control reporting is necessary.

Factors associated with higher quality of clinical practice guidelines and their recommendations for the pharmacological treatment of depression: a systematic review.

OBJECTIVE: The objective of this study was to assess the quality of clinical practice guidelines (CPGs) for the pharmacological treatment of depression along with their recommendations and factors associated with higher quality. DESIGN: We conducted a systematic review that included CPGs for the pharmacological treatment of depression in adults. DATA SOURCES: We searched for publications from 1 January 2011 to 31 December 2021, in MEDLINE, Cochrane Library, Embase, PsycINFO, BVS and 12 other databases and guideline repositories. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included CPGs containing recommendations for the pharmacological treatment of depression in adults at outpatient care setting, regardless of whether it met the U.S. National Academy of Medicine criteria, or not. If a CPG included recommendations for both children and adults, they were considered. No language restriction was applied. DATA EXTRACTION AND SYNTHESIS: Data extraction was also conducted independently and in duplicate, a process that was validated in a previous project. The quality of the CPGs and their recommendations were assessed by three independent reviewers using Appraisal of Guidelines for Research and Evaluation (AGREE II) and Appraisal of Guidelines for Research and Evaluation-Recommendations Excellence (AGREE-REX). A CPG was considered to be of high quality if AGREE II Domain 3 was ≥60%; while their recommendations were considered high if AGREE-REX Domain 1 was ≥60%. RESULTS: Seventeen out of 63 (27%) CPGs were classified as high quality, while 7 (11.1%) had high-quality recommendations. The factors associated with higher-scoring CPGs and recommendations in the multiple linear regression analyses were 'Handling of conflicts of interest', 'Multiprofessional team' and 'Type of institution'. 'Inclusion of patient representative in the team' was also associated with higher-quality recommendations. CONCLUSIONS: The involvement of professionals from diverse backgrounds, the handling of conflicts of interest, and the inclusion of patients' perspectives should be prioritised by developers aiming for high-quality CPGs for the treatment of depression.

Single-arm clinical trials that supported FDA accelerated approvals have modest effect sizes and were at high risk of bias.

OBJECTIVE: To describe effect sizes of single-arm clinical trials that supported AA approvals. STUDY DESIGN AND SETTING: We reviewed all the single-arm approvals granted by the FDA-AA pathway between June1992 to December2020. Two independent reviewers identified single-arm studies and extracted data from FDA Full-Medical Reviews. We performed a meta-analysis to estimate the effect sizes and compared it between studies that met post-approval FDA requirements for RCTs with those that did not. RESULTS: From the total of 254 approvals, single arm clinical trials describing effects of 54 drugs for 72 clinical indications were evaluated. The effect size estimated was OR:2.22(CI95%:1.76-2.81) [relative risk (RR) = 1.63(95CI% 1.38-1.92)]; 53% of treatments had a lower 95% CI bound crossing the null effect. Effect size did not differ between the treatments that met the FDA requirement for conducting post-approval RCTs. CONCLUSIONS AND RELEVANCE: Treatment effects observed in the FDA AA single-arm studies was modest and can be to ascribed to bias.

Evaluation of the initial response in clinical trial efforts for COVID-19 in Brazil. / Avaliação da resposta inicial de desenvolvimento de ensaios clínicos para COVID-19 no Brasil.

OBJECTIVE: To describe the methodological characteristics and good research practices of COVID-19 interventional studies developed in Brazil in the first months of the pandemic. METHODS: We reviewed the bulletin of the National Research Ethics Committee - Coronavirus Special Edition (Comissão Nacional de Ética em Pesquisa - CONEP-COVID) (May 28, 2020) and the databases of the International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC) to identify interventional studies registered in Brazil that assessed drug type, biological therapy, or vaccines. We described their methodological characteristics and calculated their power for different effect magnitudes. RESULTS: A total of 62 studies were included, 55 retrieved from the CONEP website, and 7 from registry databases. The most tested pharmacological interventions in these studies were: chloroquine/hydroxychloroquine, azithromycin, convalescent plasma, tocilizumab, sarilumab, eculizumab, vaccine, corticosteroids, anticoagulants, n-acetylcysteine, nitazoxanide, ivermectin, and lopinavir/ritonavir. Out of 22 protocols published on registry databases until May 2020, 18 (82%) were randomized clinical trials, and 13 (59%) had an appropriate control group. However, 9 (41%) of them were masked, and only 5 (24%) included patients diagnosed with a specific laboratory test (for example, reverse transcription polymerase chain reaction - RT-PCR). Most of these studies had power > 80% only to identify large effect sizes. In the prospective follow-up, 60% of the studies available at CONEP until May 2020 had not been published on any registry platform (ICTRP/ReBEC/ClinicalTrials) by July 21, 2020. CONCLUSION: The interventions evaluated during the Brazilian research response reflect those of international initiatives, but with a different distribution and a large number of studies assessing hydroxychloroquine/chloroquine. Limitations in methodological design and sample planning represent challenges that could affect the research outreach.

OBJETIVO: Descrever as características metodológicas e de boas práticas em pesquisa dos estudos de intervenção para COVID-19 desenvolvidos no Brasil nos primeiros meses da pandemia. MÉTODOS: Revisamos o boletim da Comissão Nacional de Ética em Pesquisa - edição especial Coronavírus (CONEP-COVID) (28 de maio de 2020) e as bases International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov e Registro Brasileiro de Ensaios Clínicos (ReBEC) para identificar estudos registrados no Brasil que avaliassem intervenções de tipo de medicamento, terapia biológica ou vacinas. Descrevemos as características metodológicas e calculamos o poder para diferentes magnitudes de efeito. RESULTADOS: Foram incluídos 62 estudos, 55 identificados no site da CONEP e mais sete nas bases de registro. As intervenções medicamentosas mais frequentemente testadas nesses estudos foram: cloroquina/hidroxicloroquina, azitromicina, plasma convalescente, tocilizumabe, sarilumabe, eculizumabe, vacina, corticoides, anticoagulantes, n-acetilcisteína, nitazoxanida, ivermectina e lopinavir/ritonavir. De 22 protocolos publicados até maio de 2020 nas bases de registro, 18 (82%) eram ensaios clínicos randomizados e 13 (59%) tinham grupo controle adequado. Entretanto, nove (41%) eram mascarados e somente cinco (24%) incluíam pacientes diagnosticados com teste de laboratório específico (por exemplo, transcrição reversa seguida de reação em cadeia da polimerase - RT-PCR). A maioria desses trabalhos teria poder > 80% apenas para identificar grandes tamanhos de efeito. Em seguimento prospectivo, observamos que 60% dos estudos disponíveis na CONEP até maio de 2020 não estavam em nenhuma das plataformas de registro (ICTRP/ReBEC/ClinicalTrials) até o dia 21 de julho de 2020. CONCLUSÃO: As intervenções avaliadas durante a resposta brasileira em pesquisa refletem iniciativas internacionais, porém com distribuição diferente, tendo número elevado de estudos que avaliam hidroxicloroquina/cloroquina. Limitações no delineamento metodológico e planejamento amostral representam desafios que podem afetar o alcance dos trabalhos.

Association Between Intra-Hospital Uncontrolled Glycemia and Health Outcomes in Patients with Diabetes: A Systematic Review of Observational Studies.

BACKGROUND: Many people are still getting affected by uncontrolled glycemic events during hospital admission, which encompasses hypoglycemia, hyperglycemia, and high glycemic variability. INTRODUCTION: Primary studies have shown an association of glycemic dysregulation with increased length of hospital stay and mortality among overall patients, however, there is no systematic review of current evidence on the association between uncontrolled in-hospital glycemia in patients with diabetes and health outcomes. This study aimed to systematically review the current evidence on the association between uncontrolled in-hospital glycemia in patients with diabetes and health outcomes. METHODS: The association between glycemic dysregulation and health outcomes for inpatients with diabetes was systematically reviewed. PubMed, Embase, and LILACS databases were searched. Two independent reviewers were involved in each of the following steps: screening titles, abstracts, and fulltexts; assessing the methodological quality; and extracting data from included reviews. Descriptive analysis method was used. RESULTS: Seven cohort studies were included, and only two had a prospective design, consisting of 7,174 hospitalized patients with diabetes. In-hospital occurrence of hypoglycemia, hyperglycemia, and glycemic variability were assessed, and outcomes were mortality, infections, renal complications, and adverse events. Among the exposure and outcomes, an association was observed between severe hypoglycemia and mortality, hyperglycemia and infection, and hyperglycemia and adverse events. CONCLUSION: In-hospital uncontrolled glycemia in patients with diabetes is associated with poor health outcomes. More studies should be conducted for proper investigation because diabetes is a complex condition. Effects of glycemic dysregulation should be investigated on the basis of overall health of a patient instead from only organ-target perspective, which makes the investigation difficult.

Evaluation of the initial response in clinical trials efforts for COVID-19 in Brazil / Avaliação da resposta inicial de desenvolvimento de ensaios clínicos para COVID-19 no Brasil

Objective: To describe the methodological characteristics and good research practices of the intervention studies for COVID-19 developed in Brazil in the first months of the pandemic. Method: A review in the CONEP-COVID bulletin (05/28/2020) and the International Clinical Trials Registry Platform, ClinicalTrials.gov, ReBEC was conducted to identify drug-type, biological therapy or vaccine intervention studies registered in Brazil. The studies were evaluated for methodological characteristics and power for different magnitudes of effect. Results: 62 studies were included, 55 identified on the CONEP website and seven on a registration database. Several interventions are being tested: chloroquine/hydroxychloroquine, azithromycin, plasma convalescent, tocilizumab, sarilumab, eculizumab, vaccine, corticoids, anticoagulants, n-acetylcysteine, nitazoxanide, ivermectin, lopinavir/ritonavir, etc. By May 2020, 22 research protocols were published in a protocol registry database, 82% were randomized clinical trials and 59% had adequate control group. However, 59% were not masked and only 24% included patients with positive test with diagnostic accuracy. Most of the studies would have power >80% just to identify large effect sizes. In a prospective follow-up, until July 21st/2020, 60% of the studies available at CONEP were not registered in the ICTRP/ReBEC/ClinicalTrials platforms. Conclusion: The interventions evaluated during the Brazilian research response reflect international initiatives, but with a different distribution, a larger proportion of studies asseessed hydroxychloroquine/chloroquine. Limitations in methodological design and sample planning represent challenges that could affect the research outreach.

Objetivo: Descrever as características metodológicas e de boas práticas em pesquisa dos estudos de intervenção para COVID-19 desenvolvidos no Brasil nos primeiros meses da pandemia. Método: Revisamos o boletim da CONEP-COVID (28/05/2020) e as bases International Clinical Trials Registry Platform, ClinicalTrials.gov e ReBEC para identificar estudos registrados no Brasil, avaliando intervenções de tipo medicamento, terapia biológica ou vacinas. Descrevemos as características metodológicas e calculamos o poder para diferentes magnitudes de efeito. Resultados: Foram incluídos 62 estudos, 55 identificados no site da CONEP e mais sete nas bases de registro. As intervenções medicamentosas mais frequentemente testadas nesses estudos foram: cloroquina/hidroxicloroquina, azitromicina, plasma convalescente, tocilizumabe, sarilumabe, eculizumabe, vacina, corticoides, anticoagulantes, n-acetilcisteína, nitazoxanida, ivermectina e lopinavir/ritonavir. De 22 protocolos, publicados até maio de 2020 nas bases de registro, 18 (82%) eram ensaios clínicos randomizados e 13 (59%) tinham grupo controle adequado. Entretanto, nove (41%) eram mascarados e somente cinco (24%) incluía pacientes diagnosticados com teste de laboratório específico (e.g. RT-PCR). A maioria desses trabalhos teria poder >80% apenas para identificar grandes tamanhos de efeito. Em seguimento prospectivo, observamos que 60% dos estudos, disponíveis na CONEP até maio de 2020, não estava em nenhuma das plataformas de registro (ICTRP/ReBEC/ClinicalTrials) até o dia 21/07/2020.Conclusão: As intervenções avaliadas durante a resposta brasileira em pesquisa refletem iniciativas internacionais, porém com uma distribuição diferente, tendo um número elevado de estudos avaliando hidroxicloroquina/ cloroquina. Limitações no delineamento metodológico e planejamento amostral representam desafios que poderiam afetar o alcance dos trabalhos.

Avaliação crítica de estudos de custo-efetividade de medicamentos oncológicos recomendados para incorporação pela Conitec no Brasil / Critical appraisal of cost-effectiveness studies of oncologic drugs recommended for incorporation by the Conitec in Brazil

Objetivo: Realizar uma análise descritiva e avaliar a qualidade metodológica das análises de custo-efetividade dos medicamentos recomendados para incorporação pela Comissão Nacional de Incorporação de Tecnologias no SUS (Conitec) para o tratamento de câncer. Métodos: Um levantamento no site da Conitec foi realizado para identificar os relatórios de recomendação para medicamentos utilizados no tratamento de câncer, datados de janeiro/2012 a junho/2019. Os relatórios dos medicamentos com recomendação para incorporação e que apresentavam estudos de avaliação econômica em saúde foram incluídos. Uma análise descritiva e da qualidade metodológica (ferramenta Consensus on Health Economic Criteria [CHEC]) foi realizada. Resultados: Dez indicações diferentes, de oito medicamentos, para tratamento de câncer foram recomendadas pela Conitec de janeiro/2012 a junho/2019, porém somente cinco (50%) dispunham de estudos de avaliação econômica. Um estudo foi excluído da avaliação da qualidade devido a limitações de acesso às informações. A qualidade metodológica foi variável nos estudos apresentados, e os domínios com pior avaliação se relacionavam a medida apropriada do desfecho e custos, discussões sobre ética, conflito de interesse e generalização dos dados. Observa-se uma falta de padronização na forma como foram realizadas as avaliações econômicas dos estudos submetidos à Conitec. Conclusão: Há grande heterogeneidade em relação à qualidade dos estudos de custo-efetividade de medicamentos oncológicos recomendados para incorporação pela Conitec e limitações metodológicas relevantes foram identificadas na maioria dos estudos

Objective: To perform a descriptive analysis and evaluate the methodological quality of the costeffectiveness studies that based the "Comissão Nacional de Incorporação de Tecnologias no SUS" (Conitec) recommendations for cancer treatment. Methods: A survey on the Conitec website was performed in order to identify the recommendation reports for anticancer drugs, from January/2012 to June/2019. Reports for new drug incorporation that presented cost-effectiveness were included and analyzed. The methodological quality of these reports was assessed with the tool Consensus on Health Economic Criteria (CHEC). Results: Ten different indications of eight anticancer drugs were recommended by Conitec from 2012 to June/2019, but only five (50%) had health economic analysis. One study was excluded from quality assessment due to limited information access. Methodological quality varies among the studies. The worst domains assessed were related to appropriate measurement of outcome and costs, ethics-related discussions, conflict of interest, and generalizability of the results. A lack of standardization was observed in Conitec's assessment on health economic studies submitted. Conclusion: There is a great heterogeneity in cost-effectiveness study quality of cancer drugs recommended by Conitec and relevant methodological limitations was noticed

Comparison of FDA accelerated vs regular pathway approvals for lung cancer treatments between 2006 and 2018.

Regulatory agencies around the world have been using flexible requirements for approval of new drugs, especially for cancer drugs. The US Food and Drug Administration (FDA) is mostly the first agency to approve new drugs worldwide, mainly due to the faster terms of the accelerated pathway and breakthrough therapy designation. Surrogate endpoints and preliminary data (e.g. single-arm and phase 2 studies) are used for these new approvals, however larger effect sizes are expected. We aim to compare FDA Accelerated vs Regular Pathway approvals and Breakthrough therapy designations (BTD) for lung cancer treatments between 2006 and 2018 regarding study design, sample size, outcome measures and effect size. We assessed the FDA database to collect data from studies that formed the basis of approvals of new drugs or indications for lung cancer spanning from 2006 to 2018. We found that accelerated pathway approvals are based on significantly more single-arm studies with small sample sizes and surrogate primary endpoints. However, effect size was not different between the pathways. A large proportion of studies used to support regular pathway approvals also showed these characteristics that are related to low quality and uncertain evidence. Compared to other approvals, BTD were more frequently based on single-arm studies. There was no significant difference in use of surrogate endpoints or sample size. 44% of BTD were based on studies demonstrating large effect sizes, proportionally more than approvals not receiving this designation. In conclusion, based on the indicators of evidence quality we extracted, criteria's for granting accelerated approval and breakthrough therapy designation seen not clear. Faster approvals are in the majority full of uncertainties which should be viewed with caution and the patient have to be communicated to allow shared decision making. Post-marketing validation is essential.

U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer.

OBJECTIVE: This paper aims to describe the clinical and regulatory aspects of new drugs and indications that were approved for lung, breast, prostate, and colorectal cancer, from 2016 to 2018, in order to provide health technology assessment trends in oncology. METHODS: Data were collected from the US Food and Drug Administration (FDA) online database for new medications and indications approved for the above-mentioned types of cancer. Data regarding clinical study characteristics and regulatory information were collected. RESULTS: From 2016 to 2018, 53 percent of the FDA approvals of new drugs and indications for the most incident cancers were for oral protein kinase inhibitor monotherapy for advanced lung cancer. Since 2018, four drugs were approved as tumor-agnostic therapies. A biomarker was included in 72 percent of indications, and 58 percent of approvals were for targeted therapies, potentially heralding an end to research into conventional cytotoxic agents. A special designation for faster approval was granted in 78 percent of new approvals. The majority of the studies were open label randomized controlled trials (RCTs) (44 percent), followed by blind RCTs, single-arm clinical trials, and cohort studies. Only 14 percent of studies used overall survival as the primary end point; the vast majority used surrogate end points, and did not use patient-important outcomes. Three biosimilars were approved in the period. CONCLUSION: Advanced lung cancer therapy, mainly targeted drugs, accounted for 53 percent of approvals. Special designations for faster approval were used in 78 percent of FDA approvals, and four drugs were approved for tumor-agnostic treatment-a new form of approval.

Medication-related inpatient falls: a critical review

Abstract Falls are the second leading cause of accidental and unintentional injury deaths worldwide. Inpatient falls in hospital settings are likely to prolong the length of stay of patients in nearly 6.3 days, leading to increased hospitalization costs. The causes of fall incidents in healthcare facilities are multifactorial in nature and certain medications use could be associated with these incidents. This review seeks to critically evaluate the available literature regarding the relationship between inpatient falls and medication use. A comprehensive search was performed on MEDLINE, EMBASE and Lilacs with no time restriction. The search was filtered using English, Spanish or Portuguese languages. Our study evaluated medication use and inpatients falls that effectively happen, considering all ages and populations. An assessment of bias and quality of the studies was carried out using an adapted tool from the literature. The drugs were classified according to the Anatomic Therapeutics Chemical Code. The search strategy retrieved 563 records, among which 23 met the eligibility criteria; ninety three different pharmacological subgroups were associated with fall incidents. Our critical review suggests that the use of central nervous system drugs (including anxiolytics; hypnotics and sedatives; antipsychotics; opioids; antiepileptics and antidepressants) has a greater likelihood of causing inpatient falls. A weak relationship was found between other pharmacological subgroups, such as diuretics, cardiovascular system-related medications, and inpatient fall. Remarkably, several problems of quality were encountered with regard to the eligible studies. Among such quality problems included retrospective design, the grouping of more than one medication in the same statistical analysis, limited external validity, problems related to medication classifications and description of potential confounders.