http www gilbertodenucci compalestrasnacionais 20 13ensaiosclinicos ppt Testes

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Testes Clínicos • Fase 0 – voluntários sadios (microdosagem) – não é regulatória • Fase I – voluntários sadios • Fase II – pacientes para prova conceitual • Fase III – grande número de pacientes – estudos multicêntricos • Fase IV – vigilância pós-mercado – pesquisa sobre novas indicações

Detecção de reações adversas Incidência esperada de uma reação adversa 1 em 100 Número de pacientes necessários para detecção do evento 1 evento 2 eventos 3 eventos 300 480 650 600 960 1. 300 1 em 1. 000 3. 000 4. 800 6. 500 1 em 2. 000 6. 000 9. 600 13. 000 1 em 10. 000 30. 000 48. 000 65. 000 1 em 200

Classificação de estudos • • • Aleatorizado (randomizado) ou não-aleatorizado. Aberto, simples-cego, duplo-cego, triplo-cego. Superioridade ou não-inferioridade Paralelo, cruzado. Controlado ou não-controlado.

Bíblia Sagrada – Tradução da CNBB – 5° edição – pag 1109 (Daniel 1 -2)

“Perhaps the most famous historical example of a planned controlled, comparative, clinical trial is from the eighteenth century: that where Lind (1753) found oranges and lemons to be the most effective of six dietary treatments for scurvy on board ships. ” - Textbook of Clinical Trials. 2004: p 03.

In 2003 Graham Sutton searched HMS Salisbury’s original papers, both the captain’s log and the separate roll-call. “However the weekly roll-call shows at most one or two, and usually none, as sick during this entire voyage”. “Lind was well aware that it was impractical to carry citrus fruits on long sea voyages because (…) oranges and lemons are liable to spoil. (…) Lind therefore devised a system of almost boiling purified citrus juice, so that 24 oranges or lemons were reduced to a few ounces. (…) Lind’s rob (fruit syrup) was later shown to be ineffective in preventing scurvy (now known because he had boiled the heat-labile ascorbic acid). “ - Nutr Rev. 2009 Jun; 67(6): 315 -32.

“Assumed to be stripped clean of human bias, the masked (blind) RCT is accepted as the gold standard and thus above scrutiny as a potential source of systematic error” - J Clin Epidemiol. 2001 Jun; 54(6): 541 -9.

J Clin Psychopharmacol. 1997 Oct; 17(5): 407 -18.

Am J Psychiatry 2006; 163: 185– 194

Medicina baseada em evidência é considerada como consenso nas diretrizes de tratamento médico. Entretanto, isso pode ser válido se a evidência for completa.

N Engl J Med 2008; 358: 252 -60

Meta-analysis: statistical alchemy for the 21 st century. Feinstein AR. J Clin Epidemiol. 1995 Jan; 48(1): 71 -9.

The p-value for each study is > 0. 20 but the p-value for summary effect is <0. 02 Introduction to Meta-Analysis – Fig 28. 1

Impact of streptokinase on mortality (adapted from Lauet al. , 1992) Introduction to Meta-Analysis – Fig 2. 1

Kidney Stones Treatment A Treatment B 78% (273/350) 83% (289/350)

Kidney Stones Large Stones Treatment A Treatment B Group 3 73% (192/263) Group 4 69% (55/80)

Kidney Stones Small Stones Treatment A Treatment B Group 1 93% (81/87) Group 2 87% (234/270)

Kidney Stones Treatment A Treatment B Small Stones Group 1 93% (81/87) Group 2 87% (234/270) Large Stones Group 3 73% (192/263) Group 4 69% (55/80) Both 78% (273/350) 83% (289/350)

Int J STD AIDS. 1999 Jan; 10(1): 8 -16. Circumcision and HIV infection: review of the literature and meta-analysis. Van Howe RS. Source Department of Pediatrics, Marshfield Clinic, Lakeland Center, USA. vanhower@dgabby. mfldclin. edu Abstract Thirty-five articles and a number of abstracts have been published in the medical literature looking at the relationship between male circumcision and HIV infection. Study designs have included geographical analysis, studies of high-risk patients, partner studies and random population surveys. Most of the studies have been conducted in Africa. A meta-analysis was performed on the 29 published articles where data were available. When the raw data are combined, a man with a circumcised penis is at greater risk of acquiring and transmitting HIV than a man with a non-circumcised penis (odds ratio (OR)=1. 06, 95% confidence interval (CI)=1. 01 -1. 12). Based on the studies published to date, recommending routine circumcision as a prophylactic measure to prevent HIV infection in Africa, or elsewhere, is scientifically unfounded. PIP: This article reviews the literature on circumcision and HIV infection. Recent studies show raw figures suggesting circumcised men to be at greater risk for HIV infection. Circumcised men have been found to also have more sexual partners. Findings explain that circumcision may be responsible for the increased number of partners, and therefore, the increased risk. In Africa, the use of dirty instruments and mass ritual events, including group circumcision, may increase the number of young boys developing HIV infections. Based on the studies published in the scientific literature, it is incorrect to assert that circumcision prevents HIV infection. Moreover, even if studies showing circumcision to be beneficial are accurate, the risk from circumcision outweighs any small benefit it may have. Thus, promoting circumcision as protection against HIV infection would lead to the belief that circumcised men are being protected from contracting AIDS, which would result in increased HIV infections.

Int J STD AIDS. 2000 Mar; 11(3): 137 -42. Circumcision in men and the prevention of HIV infection: a 'meta-analysis' revisited. O'Farrell N, Egger M. Source Department of Genitourinary Medicine, Milne Clinic, Bristol Royal Infirmary, UK. Abstract There is debate on the role of male circumcision in HIV transmission. Most case-control and cohort studies from Africa have shown an association between a lack of circumcision and an increased risk of HIV infection in men. The evidence is conflicting, however, with cross-sectional surveys from Tanzania and Rwanda either showing no relationship or an association in the opposite direction. A recent review and meta-analysis of the literature concluded that the risk of HIV infection was lower in uncircumcised men (combined odds ratio 0. 94, 95% confidence interval 0. 89 to 0. 99). However, the analysis was performed by simply pooling the data from 33 diverse studies, which is an inappropriate method for combining studies. We re-analysed the data, stratifying by study, and found that an intact foreskin was associated with an increased risk of HIV infection: combined odds ratio 1. 43 (1. 32 to 1. 54) with a fixed effect model and 1. 67 (1. 25 to 2. 24) with a random effect model. There was significant between-study heterogeneity (P<0. 0001) which was partly explained by stronger associations in studies in high-risk groups. The results from this re-analysis thus support the contention that male circumcision may offer protection against HIV infection, particularly in high-risk groups where genital ulcers and other STDs 'drive' the HIV epidemic. A systematic review is required to clarify this issue. Such a review should be based on an extensive search for relevant studies, published and unpublished, and should include a careful assessment of the design and methodological quality of studies. Much emphasis should be given to the exploration of possible sources of heterogeneity. In view of the continued high prevalence and incidence of HIV in many countries in sub-Saharan Africa, the question of whether circumcision could contribute to prevent infections is of great importance, and a sound systematic review of the available evidence should be performed without delay. Comment on The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.  Destroy user interface control  Circumcision and HIV infection: review of the literature and meta-analysis. [Int J STD AIDS. 1999]

Why Most Published Research Findings Are False John P. A. Ioannidis Summary There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

Intention-to-Treat Analysis Includes all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol (Lloyd) Fisher et al. , 1990

What is meant by intention to treat analysis? Survey of published randomised controlled trials Sally Hollis, Fiona Campbell Abstract Objectives To assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals. Conclusions The intention to treat approach is often inadequately described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses. BMJ 1999; 319: 670– 4

- Intention to treat analysis is a euphemism not to include all events in all patients from randomised until study completion. - Intention to treat analysis leads to missing data, which is one of the most catastrophic problems facing clinical trials today. - Missing data is a cancer growing on the clinical trial community.

Couto L. T; et al. Analysis of five streptokinase formulations using the euglobulin lysis test and the plasminogen activation assay. Braz J Med Biol Res 2004; 37: 1889– 1894.

Conclusion These data show that the commercially available clinical streptokinase formulations vary significantly in their in vitro activity. Whether these differences have clinical implications needs to be investigated.

CONCLUSION: There are wide variations in the activity, purity, and composition of the available streptokinase preparations.

A methodological drawback of the work by Hermentin et al. 9 (which the authors acknowledge) is the assessment of only one sample per batch of SK, limiting the generalizability of the results. Moreover, the authors have a direct interest in publicizing their findings, as the SK formulation produced and distributed by their employer showed an exemplary profile in their analyses. Despite these limits, the data by Hermentin et al. 9 appear reliable, as they are supported by another report, from an independent academic institution, using rigorous methods of analysis, which also describes marked differences in the activity of five commercially available SK formulations. 10 • • 9. Hermentin P. ; et al. Eur Heart J 2005; 26: 933– 940. 10. Couto LT. ; et al. Braz J Med Biol Res 2004; 37: 1889– 1894.

Far better an approximate answer to the right question, which is often vague, than an exact answer to the wrong question, which can always be made precise. John W. Tukey (1962)