Science-Based Approach to Harmonize Contraception Recommendations in Clinical Trials and Pharmaceutical Labels.

This review presents a European Federation of Pharmaceutical Industries and Association/PreClinical Development Expert Group (EFPIA-PDEG) topic group consensus on a data-driven approach to harmonized contraception recommendations for clinical trial protocols and product labeling. There is no international agreement in pharmaceutical clinical trial protocols or product labeling on when/if female and/or male contraception is warranted and for how long after the last dose. This absence of consensus has resulted in different recommendations among regions. For most pharmaceuticals, contraception recommendations are generally based exclusively on nonclinical data and/or mechanism. For clinical trials, contraception is the default position and is maintained for women throughout clinical development, whereas appropriate information can justify removing male contraception. Conversely, contraception is only recommended in product labeling when warranted. A base case rationale is proposed for whether or not female and/or male contraception is/are warranted, using available genotoxicity and developmental toxicity data. Contraception is generally warranted for both male and female subjects treated with mutagenic pharmaceuticals. We propose as a starting point that contraception is not typically warranted when the margin is 10-fold or greater between clinical exposure at the maximum recommended human dose and exposure at the no observed adverse effect level (NOAEL) for purely aneugenic pharmaceuticals and for pharmaceuticals that induce fetal malformations or embryo-fetal lethality. Other factors are discussed, including contraception methods, pregnancy testing, drug clearance, options for managing the absence of a developmental toxicity NOAEL, drug-drug interactions, radiopharmaceuticals, and other drug modalities. Overall, we present a data-driven rationale that can serve as a basis for consistent contraception recommendations in clinical trials and in product labeling across regions.

Comprehensive review of genotoxicity data for diclofenac.

Diclofenac is a non-steroidal anti-inflammatory drug discovered several decades ago, which has since been used by an estimated one billion patients and has demonstrated an acceptable safety profile. In support of its marketing approval, a comprehensive set of genotoxicity studies were conducted in vitro and in vivo. Despite the fact that these studies preceded both Good Laboratory Practice (GLP) requirements and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on genotoxicity testing, they were conducted using the best scientific principles and are considered appropriate by contemporary standards. In addition to bacterial mutagenicity and mammalian in vitro assays, repeat-dose somatic, germ cell and dominant lethal assays were conducted. These data are made available for the first time to offer researchers an opportunity to review the existing data set that unequivocally demonstrates that diclofenac sodium is not genotoxic. This is further substantiated by long-term bioassay data demonstrating that diclofenac sodium has no carcinogenic potential in rodents. However, more recently, new studies have been published showing a genotoxic potential for diclofenac in novel or modified in vitro test systems. These new publications are discussed in the context of the existing comprehensive data package.

Racial differences in the outcome of patients with colorectal carcinoma.

BACKGROUND: African-American (AA) patients with colorectal carcinoma have a worse prognosis compared with Caucasians. To analyze the causes of this disparity in survival, a retrospective study of patients with colorectal carcinoma was undertaken. The impact of treatments received and the role of socioeconomic factors such as income, education, and poverty levels were studied. METHODS: A retrospective analysis of patients with colorectal carcinoma at a single institution was conducted. The overall survival of AA and Caucasians, stage at presentation, treatment received, and socioeconomic factors were analyzed using the institutional tumor registry and 1990 census data. RESULTS: The overall survival of AA patients was worse compared with Caucasians, both due to all causes (P < 0.001) and cancer-related deaths (P < 0.001). The relative risk of death due to all causes was 1.4 (95% confidence interval [CI] 1.2-1.8) for AA, 4.3 for patients with Stage IV disease (95% CI 3.2-5.7), and 2.3 for patients not undergoing surgery (95% CI 1.7-3.1). After multivariate adjustment for gender, site, socioeconomic factors, and therapeutic modalities, the relative risks for death were 1.5 (95% CI 1.2) for AA, 1.4 (95% CI 1.1-1.7) for patients 60 years of age or older, and 4.2 (95% CI 3.4-5.2) for Stage IV disease. The survival difference between AA and Caucasians was not influenced by income, poverty level, and education. African Americans were treated less frequently with chemotherapy and radiation therapy compared with their Caucasian counterparts. CONCLUSIONS: African American patients with colorectal carcinoma have a poorer prognosis compared with Caucasians. This discrepancy may be due to decreased utilization of chemotherapy and radiation therapy. Socioeconomic factors and lack of access to health care do not entirely explain the worse prognosis of AA. These factors should be identified and dealt with to improve the health care of AA patients with various malignant disorders.

Evidence for vestibular regulation of autonomic functions in a mouse genetic model.

Physiological responses to changes in the gravitational field and body position, as well as symptoms of patients with anxiety-related disorders, have indicated an interrelationship between vestibular function and stress responses. However, the relative significance of cochlear and vestibular information in autonomic regulation remains unresolved because of the difficulties in distinguishing the relative contributions of other proprioceptive and interoceptive inputs, including vagal and somatic information. To investigate the role of cochlear and vestibular function in central and physiological responses, we have examined the effects of increased gravity in wild-type mice and mice lacking the POU homeodomain transcription factor Brn-3.1 (Brn-3bPou4f3). The only known phenotype of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly. Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1(-/-) mice. In line with the lack of autonomic responses, the massive increase in neuronal activity after 2G exposure normally detected in wild-type mice was virtually abolished in Brn-3.1(-/-) mice. Our results suggest that cochlear and vestibular hair cells are the primary regulators of autonomic responses to altered gravity and provide genetic evidence that these cells are sufficient to alter neural activity in regions involved in autonomic and neuroendocrine control.