Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation.

BackgroundPrevious studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications.Methods and findingsThis is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33-17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02-11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%-100%, p = 0.0039).ConclusionsMany trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased

Mechanisms of Brain Region-Specific Amyloid-beta Deposition

Alzheimer\u27s disease: AD) is the most common cause of dementia. A fundamental feature of AD is brain region-specific deposition of extracellular amyloid plaques principally comprised of the amyloid-β: Aβ) peptide. Using mouse models of cerebral Aβ deposition, we examined molecular, cellular and systems-level mechanisms that regulate brain region-specific Aβ accumulation and aggregation. Parallel studies using in vivo multiphoton microscopy and in vivo microdialysis revealed that modest pharmacological reduction of soluble interstitial fluid: ISF) Aβ levels was associated with a dramatic reduction in amyloid plaque formation and growth. We found that ISF Aβ concentrations in several brain regions of APP transgenic mice prior to the onset of plaque deposition were proportional to the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Moreover, we found that physiological modulation of endogenous neuronal activity by vibrissal manipulation was sufficient to modulate ISF Aβ levels and amyloid plaque growth dynamics. Using a novel optical intrinsic signal imaging approach, we found that bilateral functional connectivity magnitude in APP/PS1 mice prior to plaque deposition was proportional to the amount of regional plaque deposition in aged APP/PS1 mice. Furthermore, we found that bilateral functional connectivity was reduced in normal aging and was markedly exacerbated by Aβ deposition. Together, these data suggest that endogenous neuronal activity and functional connectivity may regulate region-specific Aβ plaque deposition. These data advance our understanding of the mechanisms by which the intrinsic metabolic and functional organization of the brain may contribute to AD pathogenesis

Closeness of convolutions of probability measures

We derive new explicit bounds for the total variation distance between two convolution products of $n$ probability distributions, one of which having identical convolution factors. Approximations by finite signed measures of arbitrary order are considered as well. We are interested in bounds with magic factors, i.e. roughly speaking $n$ also appears in the denominator. Special emphasis is given to the approximation by the $n$-fold convolution of the arithmetic mean of the distributions under consideration. As an application, we consider the multinomial approximation of the generalized multinomial distribution. It turns out that here the order of some bounds given in Roos (2001) and Loh (1992) can significantly be improved. In particular, it follows that a dimension factor can be dropped. Moreover, better accuracy is achieved in the context of symmetric distributions with finite support. In the course of proof, we use a basic Banach algebra technique for measures on a measurable Abelian group. Though this method was already used by Le Cam (1960), our central arguments seem to be new. We also derive new smoothness bounds for convolutions of probability distributions, which might be of independent interest.Comment: 24 page