Call to action: Harmonization of pharmacovigilance regulations for post-marketing pregnancy and breastfeeding safety studies.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the postmarketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by the TransCelerate IGR PV Pregnancy and Breastfeeding Team. The International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards and Council for International Organizations of Medical Sciences guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonization of global regulations on research in pregnant and breastfeeding women and a lack of specific regulations on this topic in the majority of the territories included in the assessment. This article focuses on the ambiguities and lack of harmonization in global regulations on postmarketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonization would facilitate more timely completion of postmarketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for women who may conceive, as well as pregnant and breastfeeding women.

Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study.

OBJECTIVE: To assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE). METHODS: A subgroup analysis was conducted in Japanese patients (n = 45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N = 1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240 mg) at week 0, followed by 120 mg every 4 weeks (120 Q4W, n = 15), 120 mg every 2 weeks (120 Q2W, n = 15), or placebo Q2W (n = 15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52. RESULTS: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p = 0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments. CONCLUSION: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo.

Regulations Governing Medicines for Maternal and Neonatal Health: A Landscape Assessment.

Limited evidence related to the safety or efficacy of medicines in pregnancy and during breastfeeding is available to inform patients and healthcare professionals. Understanding the current regulatory landscape in the clinical trial and postmarketing settings is critical to facilitate the development of applicable processes and tools for studying medicine use during pregnancy and breastfeeding and comply with health authority expectations. This review summarizes key findings from a landscape assessment of regulations, guidelines, and guidance on the use of medicines in pregnancy and breastfeeding issued by health authorities in various territories (including the Americas, Europe, Africa, and Asia Pacific) and outlines relevant initiatives undertaken by health authorities, academic institutions, industry consortia, and public-private organizations. While global pharmacovigilance legislation regarding medication use during pregnancy and breastfeeding exists and continues to evolve, the landscape assessment revealed that there is a lack of global legislative harmonization in both the clinical trial and postmarketing surveillance settings and regulatory gaps still exist in many countries/regions. Despite ongoing efforts from health authorities and public and private organizations, intensive efforts for legislation harmonization and stakeholder collaboration are required to improve the current environment of medication safety in pregnancy and breastfeeding.

Health care utilization and costs in type 2 diabetes mellitus and their association with renal impairment.

OBJECTIVE: To evaluate the health economic burden of renal impairment (RI) in patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective analysis used medical and pharmacy claims and outpatient laboratory data from a large US health care plan (January 1, 2004 to December 31, 2008). Patients with T2DM aged ≥ 18 years with continuous enrollment for ≥ 12 months pre- and post-index date (defined as date of first evidence of T2DM) who had ≥ 1 serum creatinine (SCr) laboratory test in pre- and post-index periods were included. Renal impairment prevalence was determined by laboratory data and compared with prevalence of RI identified from claims (physician-diagnosed). Renal impairment stages were categorized using estimated glomerular filtration rate. Multivariate analyses were conducted to examine association between pre-index RI status and post-index total diabetes-related health care costs. RESULTS: Of 82 263 patients with T2DM with post-index SCr laboratory values, 34.4% had RI as evidenced by laboratory data, while 11.9% had RI using claims-based criteria. The prevalence as determined from laboratory data was roughly 3 times higher than the prevalence determined from claims data, probably due to under-recognition and under-diagnosis by providers. Compared with patients without pre-index RI, patients with RI were more likely to incur ≥ 1 diabetes-related ambulatory visit (88.8% vs 85.2%; P < 0.001), emergency room visit (7.2% vs 4.5%; P < 0.001), and inpatient stay (13.8% vs 6.6%; P < 0.001) during the 12-month post-index evaluation period. Patients with pre-index RI incurred 41.8% higher post-index total diabetes-related health care costs compared with no RI (odds ratio, 1.42 [CI, 1.29-1.56]; P < 0.001). Compared with no RI, insulin-related health care costs were independently associated with increases of 37.4% (mild RI), 166.8% (moderate RI), 408.3% (severe RI), and 343.8% (end-stage RI). CONCLUSION: Renal impairment in T2DM is associated with high health care utilization and costs.

Clinical and economic outcomes associated with National Kidney Foundation guideline-concordant oral antidiabetic drug treatment among type 2 diabetes patients with chronic kidney disease.

OBJECTIVE: To assess outcomes associated with oral anti-diabetic drug (OAD) treatment concordant with guidelines from the National Kidney Foundation (NKF) among type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD). METHODS: Electronic health record data between 1/1/2005 and 10/31/2010 provided by an integrated health system were analyzed. T2DM patients were selected based on diagnosis from the health record. Patients with stages 3-5 CKD based on diagnosis or lab results were further identified with the date of first indicated CKD set as index date. Patients who had a medication order of OADs within three months of the index date were included. Patients were considered non-guideline-concordant if prescribed OADs that were recommended to be avoided or if they required dosage adjustment, but were unadjusted. Glycemic control, hospital admissions, and costs of encounters were assessed over a 12-month post-index period, and hypoglycemic events were evaluated until loss of follow-up. Regression analyses were performed, adjusting for patient demographic and clinical characteristics. RESULTS: Among 6058 patients (mean age: 70; 42% male), 45% were not [corrected] guideline-concordant. After adjusting for patient characteristics, guideline-concordant patients had a lower risk for hypoglycemic events (HR: 0.72; 95% CI: 0.62-0.83), were less likely to have a hospital admission (OR: 0.87; 95% CI: 0.77-0.98), and more likely to have glycemic control (OR: 1.64, 95% CI: 1.46-1.84). Non-guideline-concordant patients had annual encounter costs of 1.10 times those of guideline-concordant patients (marginal cost = $731; P = 0.04). LIMITATIONS: Unobservable confounders may still exist and bias the results; therefore, findings should be interpreted as associations instead of causations. Findings were based on a single integrated health system and may not be generalizable to larger populations. CONCLUSION: The findings of this exploratory study suggest that guideline-concordant treatment may yield better clinical and economic outcomes. Future research with a better controlled design is warranted to confirm these preliminary findings.

Type 2 diabetes mellitus and renal impairment in a large outpatient electronic medical records database: rates of diagnosis and antihyperglycemic medication dose adjustment.

OBJECTIVE: To assess rates of diagnosis and antihyperglycemic dose adjustment in patients with moderate to end-stage renal impairment (RI) and type 2 diabetes mellitus (T2DM). METHODS: Retrospective database analysis using GE Centricity Outpatient Electronic Medical Records. Patients aged ≥ 18 years with evidence of T2DM (International Classification of Diseases, Ninth Edition, Clinical Modification codes 250.x0 and 250.x2) between January 1, 2000 and June 30, 2009, and ≥ 12 months of data after identification were selected. Moderate to end-stage RI was evaluated using a formula-derived estimated glomerular filtration rate (eGFR) based on serum creatinine (SCr). Patients were classified as moderate (eGFR, 30-59 mL/min/1.73 m(2)), severe (eGFR, 15-29 mL/min/1.73 m(2)), or end-stage (eGFR, < 15 mL/min/1.73 m(2)), per the National Kidney Foundation guidelines, based on the first-observed SCr test. Among patients with a physician diagnosis, the time to diagnosis was reported. Dose adjustment was reported for patients receiving metformin and sitagliptin. Predictors of progression to end-stage RI based on logistic regressions were examined. RESULTS: 35.2% of patients with T2DM had evidence of moderate to end-stage RI. Of these patients, 20% had a chart-documented physician diagnosis (range, 16% [moderate RI] to 66% [end-stage RI]). Patients with moderate or severe RI had a physician diagnosis mean of 253.4 (standard deviation [SD], 584.5) and 86.9 (SD, 417.4) days, respectively, after the eGFR calculation indicating RI. Patients with end-stage RI had a physician diagnosis mean of 83.6 (SD, 399.2) days before the eGFR calculation. After the eGFR calculation, 15.1% and 0.1% of patients with orders for sitagliptin and metformin, respectively, received doses of the drug appropriate for their degree of RI. Among patients with moderate or severe RI, appropriate diagnosis of RI was associated with significantly lower odds of progressing to end-stage RI (odds ratio, 0.200; 95% confidence interval, 0.188-0.213). CONCLUSIONS: Renal impairment is common but often undetected in patients with T2DM. Patients with a documented RI diagnosis have lower odds of progression to end-stage RI. Metformin and sitagliptin are frequently used at inappropriate doses in patients with RI. Further analyses to understand the clinical and economic consequences of these findings are needed.

Ligation of CD28 by its natural ligand CD86 in the absence of TCR stimulation induces lipid raft polarization in human CD4 T cells.

Stimulation of resting CD4 T cells with anti-CD3/CD28-coated beads leads to rapid polarization of lipid rafts (LRs). It has been postulated that a major role of costimulation is to facilitate LR aggregation. CD86 is up-regulated or expressed aberrantly on immune cells in a wide array of autoimmune and infectious diseases. Using an Ig fusion with the extracellular domain of CD86 (CD86Ig) bound to a magnetic bead or K562 cells expressing CD86, we demonstrated that ligation of CD28 by its natural ligand, but not by Ab, induced polarization of LRs at the cell-bead interface of fresh human CD4 T cells in the absence of TCR ligation. This correlated with activation of Vav-1, increase of the intracellular calcium concentration, and nuclear translocation of NF-kappaB p65, but did not result in T cell proliferation or cytokine production. These studies show, for the first time, that LR polarization can occur in the absence of TCR triggering, driven solely by the CD28/CD86 interaction. This result has implications for mechanisms of T cell activation. Abnormalities in this process may alter T and B cell tolerance and susceptibility to infection.

Extensive replicative capacity of human central memory T cells.

To characterize the replicative capacity of human central memory (T(CM)) CD4 T cells, we have developed a defined culture system optimized for the ex vivo expansion of Ag-specific CD4(+) T cells. Artificial APCs (aAPCs) consisting of magnetic beads coated with Abs to HLA class II and a costimulatory Ab to CD28 were prepared; peptide-charged HLA class II tetramers were then loaded on the beads to provide Ag specificity. Influenza-specific DR*0401 CD4 T(CM) were isolated from the peripheral blood of normal donors by flow cytometry. Peptide-loaded aAPC were not sufficient to induce resting CD4 T(CM) to proliferate. In contrast, we found that the beads efficiently promoted the growth of previously activated CD4 T(CM) cells, yielding cultures with >80% Ag-specific CD4 cells after two stimulations. Further stimulation with peptide-loaded aAPC increased purity to >99% Ag-specific T cells. After in vitro culture for 3-12 wk, the flu-specific CD4 T(CM) had surface markers that were generally consistent with an effector phenotype described for CD8 T cells, except for the maintenance of CD28 expression. The T(CM) were capable of 20-40 mean population doublings in vitro, and the expanded cells produced IFN-gamma, IL-2, and TNF-alpha in response to Ag, and a subset of cells also secreted IL-4 with PMA/ionomycin treatment. In conclusion, aAPCs expand T(CM) that have extensive replicative capacity, and have potential applications in adoptive immunotherapy as well as for studying the biology of human MHC class II-restricted T cells.

Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation.

Lipid rafts are important signaling platforms in T cells. Little is known about their properties in human CD8(+) T cells. We studied polarization of lipid rafts by digital immunofluorescence microscopy in primary human T cells, using beads coated with anti-CD3 and anti-CD28 mAbs (CD3/28 beads). Unlike CD4(+) T cells, CD8(+) T cells did not polarize lipid rafts when stimulated with CD3/28 beads, when the anti-CD28 antibody was substituted with B7.2Ig, or if an anti-CD8 antibody was added to the CD3/28 beads. This phenomenon was also observed in human antigen-specific CD8(+) T cells. On stimulation with CD3/28 beads, the T cell antigen receptor clustered at the cell/bead contact area in both CD4(+) and CD8(+) T cells. Examination of lipid rafts isolated by sucrose density gradient centrifugation revealed the constitutive expression of p(56)Lck in the raft fractions of unstimulated CD8(+) T cells, whereas p(56)Lck was recruited to the raft fraction of CD4(+) T cells only after stimulation with CD3/28 beads. Stimulation with CD3/28 beads induced marked calcium flux, recruitment of PKC-theta and F-actin to the cell/bead contact site, and similar proliferation patterns in CD4(+) and CD8(+) T cells. Thus, polarization of lipid rafts is not essential for early signal transduction events or proliferation of human CD8(+) lymphocytes. It is possible that the lower stringency of CD8(+) T cell activation obviates a requirement for raft polarization.