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Purpose: Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype., Methods: Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and "other patients" (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb 3 )., Results: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFR CKD-EPI with migalastat was -0.3 (3.76) mL/min/1.73 m 2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb 3 were -16.7 (18.64) g/m 2 , -0.9 (1.66), and -36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with migalastat (-0.8) and increased with placebo (0.3); switching from placebo to migalastat, PTC inclusions decreased by -0.7. Numerically smaller changes in these endpoints were observed in the other patients., Conclusion: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

We examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials. We focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005-2010. We contrasted these findings with those from 2 different groups: 1. diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2. diabetes drugs with NDAs delayed and not yet approved within the same time frame (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release). The new guidelines have had an important impact on clinical development. Review time has increased over 2-fold. The increase is seen even if a drug with the same mechanism of action has been already approved. Whereas exenatide (approved in 2005) required 10 months of regulatory review, the approval of liraglutide in 2010 required more than twice as long (21 months). In contrast, the marketing authorization of liraglutide in the EU required 14 months. Additionally, the manufacturer of vildagliptin announced in June 2008, 30 months after the NDA was filed, that a re-submission to meet FDA's demands was not planned. The drug however received marketing authorization in the EU in 2007. The number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines. The significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We compared the clinical trial transparency practices of US/European pharma by analyzing the publicly-accessible clinical trial results databases of major drugs (doripenem, varenicline, lapatinib, zoledronic acid, adalimumab, insulin glargine, raltegravir, gefitinib). We evaluated their accessibility and utility from the perspective of the lay public. We included databases on company websites, http://www.clinicalstudyresults.org, http://www.clinicaltrials.gov and http://clinicaltrials.ifpma.org. Only 2 of 8 company homepages provide a direct link to the results. While the use of common terms on company search engines led to results for 5 of the 8 drugs following 2-4 clicks, no logical pathway was identified. The number of clinical trials in the databases was inconsistent: 0 for doripenem to 45 for insulin glargine. Results from all phases of clinical development were provided for 2 (insulin glargine and gefitinib) of the 8 drugs. Analyses of phase III reports revealed that most critical elements of the International Conference of Harmonization E3 Structure and Content of Synopses for Clinical Trial Reports were provided for 2 (varenicline, lapatinib) of the 8 drugs. For adalimumab and zoledronic acid, only citations were provided, which the lay public would be unable to access. None of the clinical trial reports was written in lay language. User-friendly support, when provided, was of marginal benefit. Only 1 of the databases (gefitinib) permitted the user to find the most recently updated reports. None of the glossaries included explanations for adverse events or statistical methodology. In conclusion, our study indicates that the public faces significant hurdles in finding and understanding clinical trial results databases.