Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study.

AIMS: Previously, a retrospective cohort study found no increased risk of acute pancreatitis with current or recent use of exenatide twice daily compared with use of other anti-diabetic drugs. This follow-up study investigated incident acute pancreatitis, with the use of a different data source and analytic method, in patients exposed to exenatide twice daily compared with patients exposed to other anti-diabetic medications. METHODS: A large US health insurance claims database was used. Eligible patients had ≥ 9 months continuous enrollment without a claim for pancreatitis and a claim for a new anti-diabetic medication on or after 1 June 2005 to 31 March 2009. Cases of acute pancreatitis were defined as hospitalized patients with an Internation Classification of Disease 9 code of 577.0 in the primary position. A discrete time survival model was used to evaluate the relationship between exenatide twice daily and acute pancreatitis. RESULTS: Of 482,034 eligible patients, 24,237 initiated exenatide twice daily and 457,797 initiated another anti-diabetic medication. Initiators of exenatide twice daily had more severe diabetes compared with initiators of other anti-diabetic medications. After adjustments for propensity score, insulin and use of medication potentially associated with acute pancreatitis, the odds ratio with exenatide twice daily exposure was 0.95 (95% CI 0.65-1.38). A secondary analysis that examined current, recent and past medication exposure found no increased risk of acute pancreatitis with exenatide twice daily, regardless of exposure category. CONCLUSION: This study indicates that exposure to exenatide twice daily was not associated with an increased risk of acute pancreatitis compared with exposure to other anti-diabetic medications. These results should be interpreted in light of potential residual confounding and unknown biases.

A cohort study of acute pancreatitis in relation to exenatide use.

AIM: Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs. METHODS: This cohort study included patients without claims for prior pancreatic disease who initiated exenatide or other antihyperglycaemic drugs between June 2005 and December 2007. Acute pancreatitis was identified with diagnosis codes and confirmed through review of blinded medical records. Poisson regression models provided estimates of rate ratios (RRs) and 95% confidence intervals (CIs) comparing the rate of acute pancreatitis during periods of current (days supplied + 31 days), recent (current definition + 31 days) and past use (≥32 days beyond current definition) of exenatide relative to other antihyperglycaemic drugs, adjusted for propensity scores. A prespecified nested case-control analysis provided RR estimates adjusted for patient characteristics abstracted from medical records. RESULTS: Initiators of exenatide (N = 25719) had more baseline claims for obesity and concomitant diabetes drugs than comparators (N = 234536). There were 40 confirmed cases of acute pancreatitis in the exenatide cohort and 254 among other antihyperglycaemic drug initiators. Compared to other antihyperglycaemic drugs, the propensity score-adjusted RR for exenatide was 0.5 (95% CI 0.2-0.9) for current use, 1.1 (95% CI 0.4-3.2) for recent use and 2.8 (95% CI 1.6-4.7) for past use. The case-control analysis resulted in a RR of 0.2 for current use (95% CI 0.0-1.4) and 0.1 for recent use (95% CI 0.0-1.3), but an attenuated RR in the past use association (RR 1.1; 95% CI 0.1-11.0). CONCLUSIONS: Exenatide use was not associated with an increased risk of acute pancreatitis.

Application of the BRAT framework to case studies: observations and insights.

The BRAT Framework is a set of flexible processes and tools that provides a structured approach to pharmaceutical benefit-risk decision making in drug development and post approval settings. A work in progress, it consists of six steps that produce representations of key tradeoffs, with appropriate documentation of the rationale for decisions and the assumptions made in their development. This article describes insights, gained from case studies, into the Framework's performance in a variety of constructed benefit-risk scenarios, focusing on a hypothetical example of a triptan for migraine. The scenarios described illustrate the challenges inherent in arriving at many of the regulatory decisions, including obtaining data for matching populations for all outcomes, finding data of consistent quality, addressing correlated outcomes (e.g., elevated liver function tests and hepatitis rates), dealing with rare but serious adverse events (AEs), and understanding and making decisions based on information for many outcomes simultaneously. The Framework provides a structure for organizing, interpreting, and communicating relevant information, including heterogeneity in results and the quality and level of uncertainty of data, in order to facilitate benefit-risk decisions.

In vivo and in vitro gene transfer and expression in rat intestinal epithelial cells by E1-deleted adenoviral vector.

The intestine is proposed to be an attractive target site for somatic gene therapy due to a large mass of proliferating tissue and stem cells in the crypts. Previous studies using a retroviral vector have shown that a reporter gene, bacterial beta-galactosidase (beta-Gal), can be transferred and expressed in the small intestinal epithelial cell. However, transduction efficiency is relatively low in rat and mice intestines. In the present study, we employed an E1-deleted adenoviral vector (which encodes the beta-Gal gene) to investigate the feasibility of gene transfer into rat small intestinal epithelial cell lines and small intestines in male Sprague-Dawley rats. In in vitro studies, expression of AdCMV beta gal was quantitatively measured in IEC-6 and IEC-18 cell cultures using X-Gal histochemistry and chemiluminescent reporter gene assays. The results indicate that AdCMV beta gal can be efficiently transferred into intestinal epithelial cell lines and transgene expression is virus concentration dependent. In in vivo studies, a 5F intestinal feeding tube was used to deliver the vector to the duodenal segment of the rat. Expression of AdCMV beta gal was primarily localized to the epithelium of the intestinal tract. Transduction efficiency of the transgene was seen in the duodenum, jejunum, ileum, and, to a lesser extent, the colon. Moreover, following a single or secondary administration of recombinant adenovirus, efficient expression of AdCMV beta gal in the intestinal tract peaked at 3 days and decreased by 7 and 14 days. No antiadenoviral antibody response was detected in the serum after a single or secondary challenge with this virus. These findings demonstrate that an E1-deleted adenoviral vector, when administered through an oral-duodenal tube, transfers genetic material more successfully in the intestinal epithelium in the small intestine when compared to the large intestine. A single or secondary challenge with adenoviral vector does not cause enhanced host immune responses to this virus. It suggests that successful gene transduction by the repeat administration of the adenoviral vector makes it an alternative candidate for gene therapy applications in intestinal diseases and metabolic deficiencies.

Optimization of gene transfer into intestinal epithelial cells using a retroviral vector.

Somatic gene therapy has been proposed as a method of treating various metabolic diseases and conditions associated with a deficiency in secretory proteins. The intestine, because of its accessibility, large size, rapid rate of cell turnover, and known location of stem cells, is an attractive site for retroviral gene therapy. Stem cells in the intestine are known to reside in the crypts of Lieberkühn. In this study the IEC-6 cell line, derived from rat intestinal crypt cells, was used as an in vitro model to study the feasibility and dynamics of retroviral gene transfer in intestinal cells. Using a replication-deficient retrovirus, we delivered a reporter gene, bacterial beta-galactosidase (beta-gal) into NIH-3T3 fibroblasts and IEC-6 cells. Successful transduction was measured by X-gal histochemistry. Viral titers on IEC-6 cells were lower than on NIH-3T3 cells but were within the same order of magnitude. Gene transfer increased linearly with retroviral concentration up to a 1:5 dilution of retroviral supernatant. With undiluted viral medium, gene transfer was inhibited and this effect was more pronounced with the IEC-6 cells. The negative effect of the undiluted retroviral supernatant was minimized by decreasing the harvest time from the packaging cell line. An optimal plating density 12 h prior to infection was found to be approximately 10(5) cells/6-cm dish in both cell lines. The infection rate was proportionally enhanced by the use of multiple infections. In conclusion, under ideal conditions, the IEC-6 cells were infected at similar levels of efficacy as NIH-3T3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)