OdE1

Lipids contribute significantly to the pathogenesis of fungal infectious diseases and an understanding of lipid metabolism occurring in fungal pathogens can help the development of more efficient antifungal therapeutic strategies. In this study, the effect of culture age on the distribution of fatty acids among different neutral lipid (NL) classes in the dimorphic fungus Histoplasma capsulatum was investigated. Yeast cells of the G217B strain grown in two different media were collected after 4 and 7 days of growth, which roughly correspond to log and stationary culture growth phases, respectively. Neither culture age nor medium type had any influence on qualitative fatty acid (FA) profiles; however, the FA percentage composition varied with culture growth. A culture age-related decrease in the content of unsaturated FAs could be observed in all four of the NL classes examined, but the most intensive changes were detected in diacylglycerol and free FA fractions. Conversely, an increase in saturated FAs was observed. The transcriptional analysis of two major delta 9- and delta 12-FA desaturase genes, ode1 and sde1, showed no differences in their expression levels under experimental conditions. These results showing the dynamics of changes in FA composition in the NL fraction were concomitant with nutrient exhaustion in aging H. capsulatum cultures. Overall, the results presented in this work not only have implications for our knowledge of basic lipid biochemistry of H. capsulatum, but also will contribute to better understanding of biology and pathogenesis of this fungus and, consequently, can help in the discovery of more effective antifungal drugs.

Dr Robert Temple is Director of the Office of Medical Policy of FDA's Center for Drug Evaluation and Research and is also Acting Director of the Office of Drug Evaluation I (ODE-I). He has served in this capacity since the office's establishment in 1995. Dr Temple received his medical degree from the New York University School of Medicine in 1967. In 1972, he joined CDER as a review Medical Officer in the Division of Metabolic and Endocrine Drug Products. He later moved into the position of Director of the Division of Cardio-Renal Drug Products. In his current position, Dr Temple oversees ODE-1, which is responsible for the regulation of cardio-renal, neuropharmacologic and psychopharmacologic drug products. He also oversees The Office of Medical Policy, which is responsible for regulation of promotion through the Division of Drug Marketing, Advertising and Communication and for assessing quality of clinical trials. Dr Temple has a long-standing interest in the design and conduct of clinical trials and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active control trials, trials to evaluate dose-response and trials using 'enrichment' designs.

Purpose: Standardised MedDRA Queries (SMQs) have been developed since the early 2000's and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA). Methods: We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed. Results: A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with "narrow terms" to enhance specificity over strategies using "broad terms" to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision-making process. Conclusions: SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions.