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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction:: The effectiveness of the treatment of chronic diseases depends on the participation of the patient, influenced by different sociocultural factors, which are not fully recognized by the treatment routine., Objective:: To search for some of these factors that hinder or facilitate adherence to treatment and use of healthcare resources, approaching patients with ischemic heart disease., Method:: A cross-sectional study was conducted using face-to-face interviews. We applied semi-structured questionnaires to 347 individuals and recorded 141 interviews for qualitative analysis. Descriptors were selected to identify eight categories of analyses. The quantitative data were submitted to descriptive analysis of frequency., Results:: Only 2% had good medication adherence according to score on Morisky questionnaire. About 23% bought statins; the others obtained statin in the public health institution. Thirty-six speeches were selected and classified according to the following categories: knowledge about disease and medication, difficulty of acquisition, self management of treatment, difficulties of access to health services, side effect of statins, caregiver support, transportation to health services and concerns about the disease progression. However, it was noticed that about 1/3 of the care outside the research institution can be characterized as an attempt to bring rationalization to the health system., Conclusion:: The improved adherence to chronic treatment of ischemic heart disease depends on the establishment of effective flows for referral and counter-referral from one care unit to another, relevant information and clarification of the questions for the patients and the attention of health professionals to the many social and cultural factors involved in treatment adherence. New research should be focused on educational groups by integrated multidisciplinary teams in order to share treatment decisions, thereby increasing the patient's commitment to his own health.

Background: Surrogate endpoints may be used as substitutes for, but often do not predict clinically relevant events. Objective To assess the methodological quality of articles that present their conclusions based on clinically relevant or surrogate outcomes in a systematic review of randomised trials and cohort studies of patients with rheumatoid arthritis treated with antitumour necrosis factor (TNF) agents., Methods: PubMed, Embase and Cochrane databases were searched. The Jadad score, the percentage of Consolidated Standards Of Reporting Trials (CONSORT) statement items adequately reported and levels-of-evidence (Center for Evidence-based Medicine, Oxford) were used in a descriptive synthesis., Results: Among 88 articles appraised, 27 had surrogate endpoints, mainly radiographic, and 44 were duplicate publications; 74% of articles with surrogate and 39% of articles with clinical endpoints (p=0.006). Fewer articles with surrogate endpoints represented a high level of evidence (Level 1b, 33% vs 62%, p=0.037) and the mean percentage of CONSORT statement items met was also lower for articles with surrogate endpoints (62.5 vs 70.7, p=0.026). Although fewer articles with surrogate endpoints were randomised trials (63% vs 74%, p=0.307) and articles with surrogate endpoints had lower Jadad scores (3.0 vs 3.2, p=0.538), these differences were not statistically significant., Conclusion: Studies of anti-TNF agents that report surrogate outcomes are of lesser methodological quality. As such, inclusion of such studies in evidence syntheses may bias results.

Objective: The increasing use of opioids by patients suffering from chronic pain caused by different etiologies, and the possible effects of those substances on everyday activities, require careful evaluation of their effects. For this purpose, a systematic review was developed to assess the influence of opioids on the cognitive function in patients with chronic pain., Methods: Eleven databases were analyzed using the following descriptors: opioids, opiates, narcotics, cognitive impairment, cognitive dysfunction, cognitive disorders and pain. The inclusion criteria were: clinical trials or case reports which included patients with chronic pain in treatment with opioids, cognitive assessment by specific tests and publication in English, Spanish or Portuguese., Results: Sixteen surveys published between 1980 and 2004 met the criteria: six controlled trials, two randomized trials, and 10 studies of a lower scientific evidence level. All better quality controlled trials did not show cognitive impairment of patients under opioid therapy., Conclusion: These results must be confirmed by additional randomized trials including a greater number of patients with chronic pain.

Evidence based practice is the use of the best scientific evidence to support the clinical decision making. The identification of the best evidence requires the construction of an appropriate research question and review of the literature. This article describes the use of the PICO strategy for the construction of the research question and bibliographical search.

Background: To study the prevalence of cardiovascular risk associated to the lifestyle of school children from the 5th to 8th grade, in public and private schools., Methods: Eighty seven randomly selected school rooms were visited adding up to 2,125 students who completed the questionnaire and whose body mass index was calculated. This sample represents around 2% of students from two school districts in the city of Sao Paulo., Results: Of the 2,125 students, 24% were overweight or obese, 53.3% presented inappropriate food habits, 15.4% were sedentary, 62.6% drank alcohol, and 23.1% smoked. Between the 5th and 8th grade, the number of students who drank alcohol doubled and the number of male and female adolescents who tried out smoking increased 3-fold and 5-fold, respectively. Conversely, inappropriate food habits decreased. This situation is found in 40% of students from public schools and in 58% of those in private schools, by the time they reach the 8th grade. Overweight and obesity are more prevalent in private schools and the reduction noted as grades progress did not reach a significance level. Sedentarism is more prevalent in public schools. In private ones, sedentarism is lower among older students, contrary to public schools, where it increases with age. Female adolescents attend fewer physical education classes. Inappropriate food habits were characterized by the habits of adding more salt to pre-prepared food, lower intake of dairy products, fruit and vegetables also a higher intake of soft drinks, butter and snacks., Conclusion: Early detection of these cardiovascular risks associated to the lifestyle of these school children endorses the preventive practice of providing health education in schools.

Evidence based health care begins with a clinical question and the search on data bases to retrieve the relevant information, that was the issue of two preceding articles of this series. At present it will be discussed how to critically appraise the medical literature using the clinical epidemiological methodology. Clinical research aims to develop diagnostic and therapeutic procedures measuring association and causality between the exposure and outcome. In this case the exposures are signs, symptoms, laboratorial or image exam, and therapy intervention. It is a mistake to take surrogate end-points instead of clinical outcomes. The main types of clinical study design are diagnostic, prognostic, therapeutic and harm/etiology. Experimental, physiologic and animal studies are useful for the medical undergraduate education, but do not contribute with clinical decisions. The study designs are classified according with the presence of a control group, patient's follow-up, and therapy interventions. The evidence hierarchy was done by the previous characteristics and the presence of systematic bias. Systematic reviews are stronger than the primary observational studies and are on the top when they revised randomized clinical trial. Since 1998 the proportion of evidence based practice guidelines was increasing compared with systematic reviews or other types of practice guidelines, although the former still are in a few numbers. The article critical appraisal must answer the clinical question, and need to have consistent study design and bias under control. In conclusion we ought to offer methodological actualization to interested physicians and put the information already critically assessed on evidence-based practice guidelines.

The inadequacy of most of traditional sources for medical information, like textbook and review article, do not sustained the clinical decision based on the best evidence current available, exposing the patient to a unnecessary risk. Although not integrated around clinical problem areas in the convenient way of textbooks, current best evidence from specific studies of clinical problems can be found in an increasing number of Internet and electronic databases. The sources that have already undergone rigorous critical appraisal are classified as secondary information sources, others that provide access to original article or abstract, as primary information source, where the quality assessment of the article rely on the clinician oneself . The most useful primary information source are SciELO, the online collection of Brazilian scientific journals, and Medline, the most comprehensive database of the USA National Library of Medicine, where the search may start with use of keywords, that were obtained at the structured answer construction (P.I.C.O.), with the addition of boolean operators "AND", "OR", "NOT". Between the secondary information sources, some of them provide critically appraised articles, like ACP Journal Club, Evidence Based Medicine and InfoPOEMs, others provide evidences organized as online texts, such as "Clinical Evidence" and "UpToDate", and finally, Cochrane Library are composed by systematic reviews of randomized controlled trials. To get studies that could answer the clinical question is part of a mindful practice, that is, becoming quicker and quicker and dynamic with the use of PDAs, Palmtops and Notebooks.

Clinical decisions in daily practice, to resolve patient's problem, are usually based at the conscious use of the available information, through explicit determined rules. Evidence based clinical practice recognize the explicit and tacit knowledge, understanding that it is impossible all the aspects of professional competence become explicit. The doubt becomes part of the decision process, identifying initially the unconscious component involved and after the explicit knowledge used. When we make a structured clinical question with a possible answer, it is necessary to remember that the doubt can be related to basics and of definition aspects of the disease or related to the patient's manager, like diagnose, treatment and prognosis. Along our medical life, both types of question are present, with proportional change as the experience increase along the clinical practice. The process to find an appropriate answer to the doubt, came out at patient's care, depends on how the parts of this process will be structured. The recommended form is known by PICO abbreviation, that means: P: patient or population, I: intervention or indicator, C: comparison or control and O: outcome, or the answer expected found at the scientific information bases. This is the first basic need to a successful search, and the second need is to find the key words that better describe each of the four components of the questions. Without this caution, the search at compute databases results in absence of information or in a lot of information that it is not related to our interest.