Epidemiologia Clinica Fletcher Pdf 31
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Coagulation factors are expensive pharmaceutical products. In Brazil they are acquired directly by the Ministry of Health, and in 2019 alone, the federal government made available BRL 1.3 billion for the purchase of medicines for the treatment of hereditary hemorrhagic diseases for the Public Health System (SUS - Sistema Único de Saúde).(7)The costs of a medicine depend on several factors, such as the technology used in the development and production process, as well as its proven efficacy and magnitude of benefits found in phase III clinical trials. Thus, through the evaluation of all documentation made available by pharmaceutical companies to request a medicine registration, regulatory agencies assess whether this new product is effective and safe, and whether the cost-benefit ratio is positive, as it is necessary to rationalize the health system resources.(8,9)
The gold standard design for measuring intervention effects is the Randomized Clinical Trial, since this research design has strict methodological criteria, and parameters that allow controlling the influence of various factors on the investigated outcome.(13) However, it is important to highlight that non-randomized, uncontrolled clinical studies, with no blinding, and other systematic errors have increased and are being used as a technical scientific basis for the approval of new treatments.(14) These methodological flaws, which are called biases, may overestimate the benefits of the tested intervention, which can compromise the reliable analysis of the results and give the industries margins to increase the costs of these products.(15,16)
Individual analysis of the methodological quality of eligible clinical trials was performed using the Cochrane Collaboration 5.1.0 risk and bias tool. This tool consists of seven domains: - random sequence generation; - allocation concealment; - blinding of participants and professionals; - blinding of outcome evaluators; - incomplete outcomes; - selective outcome reporting; and - other sources of bias - for this domain, the conflict of interest in the analyzed studies was evaluated.(19,20)
Most studies analyzed did not control for performance bias and detection bias. It is important to emphasize that blinding is only possible in studies with Control Groups, as the results of outcomes assessed in single-arm studies are only those of the applied intervention.(36) Of the five studies that used Control Groups, only two were with blinded outcome evaluators, and three with blinded participants and professionals. According to Buehler et al.,(34) and Kamper(37) it is not always possible to apply blinding, possibly because it is difficult to perform blinding in studies that assess the efficacy and safety of coagulation factors for the treatment of hemophilia, as they are injectable preparations. On the other hand, some alternatives could have been used to overcome this barrier, like those used in the study by Sjamsoedin et al.,(25) such as coding interventions and using dark colored bottles and opaque syringes. The absence of blinding in clinical trials directly implies the estimation of the effect of the evaluated outcome. Schulz et al.(36) evaluated the impact of methodological quality on the effect estimate and showed that studies that were not double-blind produced effect estimates 17% higher than those that were double-blind. In this context, it is clear that once again, the results reported in the studies contained in the coagulation factors package inserts may not be as encouraging, as the reported effect estimates may also have been influenced by the performance and detection bias.
Moreover, a positive point of the analyzed studies is that all of them controlled the reporting bias, as they presented a low risk of bias in the selective outcome report domain. Controlling reporting bias is essential so that there are no deviations in study protocols, such as the inversion of clinical outcomes (primary) by substitute (secondary) outcomes. This can occur intentionally, when, e.g., the authors assess multiple outcomes but report only those that had positive effects, leading to erroneous conclusions as for the efficacy of the studied intervention.(11,39) Therefore, it is notable that the authors reported the proposed primary and secondary outcomes, thus evidencing results that are of interest to the perspectives of health professionals and patients.
Furthermore, this research evidenced that half of the studies showed a conflict of interest for financing from companies interested in the approval of the medicine. Palma et al.,(40) bring in their study a reflection that the interest of the pharmaceutical industry in research, production, dissemination, and commercialization of medicines is a reality all over the world. A study conducted by Santos et al.(41) explained that the conflict of interest was present in most of the studies analyzed and that funding by the pharmaceutical industry was associated with conclusions favorable to the treatment being tested. That said, it is crucial to critically analyze the results of clinical trials where industry funding is available, as this study design is largely dependent on rigorous methods to control bias, and any deviation, whether intentional or not, can influence in an increase in the estimated effect of the evaluated outcome.
Before requesting the registration of a drug, the pharmaceutical industry must comply with current legislation and present to regulatory agencies documentation containing pre-clinical and clinical studies to prove efficacy and safety, in addition to administrative technical issues, such as certificates of good manufacturing practices. It is also responsibility of the industry to prepare the package insert.(9) The Collegiate Board of Directors Resolution (RDC) # 47 of 2009(11) regulates, standardizes, and assists in the preparation and updating of information on medicine package inserts in the country. This resolution provides that the reference, generic and similar package inserts, intended to health professionals, must describe the results of the studies used to prove the efficacy and registration of the drug, as well as bibliographical references of the cited studies.
This study brings worrying data as for the quality of technical information present in the package inserts for coagulation factors, showing that 10 of the 17 package inserts selected for health professionals do not refer to the described efficacy studies. The RDC # 47 of 2009,(11) which standardizes and assists in the preparation and updating of information on medicine package inserts for patients and health professionals, establishes that the described efficacy results must cite the bibliographic references used. Marques et al.(42) reinforce that in order not to negatively compromise the evidence-based clinical practice, a greater commitment of the industries in the adaptation to the current legislation for the production of package inserts, and greater rigor in the approval and inspection of these by the sanitary regulatory agencies is necessary. In this context, ANVISA needs to review and update the package inserts of products containing coagulation factors for the treatment of hemophilia in Brazil, so that health professionals have available quality and updated information, to enable them to seek the primary sources of the cited scientific evidence, allowing them to make a critical analysis of each of the studies used for the approval and use of the medicine.
We made use of 10 previously published GWAS (Supplementary Data 2): (1) UK1 (CORGI study) comprised 940 cases with colorectal neoplasia and 965 controls12; (2) Scotland1 (COGS study) included 1012 CRC cases and 1012 controls12; (3) VQ58 comprised 1800 cases from the UK-based VICTOR and QUASAR2 adjuvant chemotherapy clinical trials and 2690 population control genotypes from the Wellcome Trust Case Control Consortium 2 (WTCCC2) 1958 birth cohort50; (4) CCFR1 comprised 1290 familial CRC cases and 1055 controls from the Colon Cancer Family Registry (CCFR)15; (5) CCFR2 included a further 796 cases from the CCFR and 2236 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) studies of breast and prostate cancer51,52; (6) COIN was based on 2244 CRC cases ascertained through two independent Medical Research Council clinical trials of advanced/metastatic CRC (COIN and COIN-B)53 and controls comprised 2162 individuals from the UK Blood Service Control Group genotyped as part of the WTCCC2; (7) Finnish GWAS (FIN)3 was based on 1172 CRC cases and 8266 cancer-free controls ascertained through FINRISK, Health 2000, Finnish Twin Cohort and Helsinki Birth Cohort Studies; (8) CORSA (COloRectal cancer Study of Austria) a molecular epidemiological study of 978 cases and 855 colonoscopy-negative controls54; (9) DACHS (Darmkrebs: Chancen der Verhütung durch Screening)55 based on 1105 cases and 700 controls and (10) Croatia consisted of 764 cases and 460 population-based controls56.
The SCOT data can be requested through the TransSCOT committee according to the ethical permissions obtained as part of the clinical trial approval. The PRACTICAL and BCAC consortium control data are available through the respective Data Access Coordination Committees ( and ) and the Heinz Nixdorf Recall Study control data can be requested through -due.de/recall-studie/die-studien/hnr/. UK Biobank data can be obtained through The Colon Cancer Family Registry data can be obtained through
The relevance of evidence-based practice in speech therapy, and in all areas of health, is currently widely recognized, since it can directly impact the quality of health care11. Miranda VSG, Marcolino MAZ, Rech RS, Barbosa LR, Fischer GB. Evidence-based speech therapy: the role of systematic revisions. CoDAS. 2019;31(2):e20180167.. In this context, there is a growing production of systematic reviews, and the search for quality in its development aims to improve the scientific production of speech therapy and its influence on the decision of clinical speech therapists and health managers. Systematic reviews may include meta-analyzes, a statistical technique used to combine the results of different individual studies into a single, metanalytical summary measure22. Fletcher RH, Fletcher SW. Epidemiologia clínica: elementos essenciais; tradução Roberta Marchiori Martins. Porto Alegre, Artmed, 2006.. 153554b96e
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