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.

Improving the decision-making process for nonprescription drugs: a framework for benefit-risk assessment.

Nonprescription drugs pose unique challenges to regulators. The fact that the barriers to access are lower for nonprescription drugs as compared with prescription drugs may permit additional consumers to obtain effective drugs. However, the use of these drugs by consumers in the absence of supervision by a health-care professional may result in unacceptable rates of misuse and suboptimal clinical outcomes. A value-tree method is proposed that defines important benefit and risk domains relevant to nonprescription drugs. This value tree can be used to comprehensively identify product-specific attributes in each domain and can also support formal benefit-risk assessment using a variety of tools. This is illustrated here, using a modification of the International Risk Governance Council (IRGC) framework, a flexible tool previously applied in a number of fields, which systematizes an approach to issue review, early alignment of stakeholders, evaluation, and risk mitigation/management. The proposed approach has the potential to provide structured, transparent tools for regulatory decision making for nonprescription drugs.

The changing character of regulation: a comparison of Europe and the United States.

European and U.S. regulatory policies have changed considerably over the past 30 years. In Europe, since the mid-1980s, consumer and environmental regulation has become more politically salient and regulations have by and large become stricter. On the other hand, in the United States consumer and environmental issues have become less salient and contentious, and regulations have not become (comparatively) stricter. This apparent "flip-flop" of regulatory systems has not been analyzed in much detail to date. This perspective is an attempt to analyze some examples in which it has occurred and identifies one possible cause--namely, credibility.

Risk management across the globe: insights from a comparative look at Sweden, Japan, and the United States.

In light of the present day risk controversies such as global warming and hormones in beef, partially caused by a more globalized world, national differences and similarities in how to manage risks become increasingly important. In this brief "perspective" we focus on how risks are managed in three nations, namely Japan, Sweden, and the United States, specifically focusing on the roles of deliberation, risk analysis, and the importance of cultural factors.

Measuring sphere-like structures using transrectal ultrasonography.

Sphere-like structures are commonly measured for clinical or research purposes. We measured two diameters, the circumference (perimeter) and cross sectional area of 113 equine ovarian follicles in a water bath then determined the relationships between those measurements and the actual volume of fluid in the follicles. Cross-sectional area, diameter3 and area2/3 were all highly correlated with the volume of the structures and superior (p < 0.05) to diameter or perimeter as predictors of volume. As predictors of volume, there was no significant difference (p > 0.05) between cross-sectional area, diameter3, and area2/3. Because of the ease of measuring diameter, we suggest that diameter3 be used to estimate the actual size of sphere-like structures by ultrasonographic measurement. A table was generated for clinical use to show how much the largest diameter of a fluid-filled structure (follicle, cyst, hematoma, etc.) would have to increase or decrease to indicate a significant change in the volume of the structure.

Detection of bovine herpesvirus 1 in the semen of experimentally infected bulls by dot-blot hybridisation, polymerase chain reaction and virus isolation.

Two 18-month-old bovine herpesvirus 1 (BHV1)-seronegative bulls were inoculated experimentally with BHV1 via their prepuces. Semen collected at intervals was examined by optimised virus isolation, dot-blot hybridisation and the polymerase chain reaction (PCR) for detection of BHV1, and the infection was monitored serologically by using a virus neutralisation test. Antibodies were first detected 10 days after inoculation and were still present 40 days after inoculation. Semen collected from four to 40 days after inoculation was positive by PCR with Southern blot hybridisation whereas only the semen collected on day 4 was positive by dot-blot hybridisation, virus isolation and PCR with ethidium bromide staining. These results indicate that the bulls started to shed the virus in semen before they developed any detectable antibody. PCR with Southern blot hybridisation was the most sensitive of the three methods and detected virus for the longest period.

Prolonged proestrus in a bitch with X chromosomal monosomy (77,XO).

A stunted Miniature American Eskimo bitch that had signs of proestrus, which persisted for almost 8 months, had a 77,XO karyotype. Despite signs of proestrus, the ovaries were small and fibrous, and there was no evidence of ovarian follicle development or corpora lutea. Except for its juvenile appearance, the rest of the reproductive tract was grossly normal. Clinical signs in this bitch were similar to those in human beings with Turner's syndrome.

Urinary eCG patterns in the mare during pregnancy.

Blood and urine samples collected from 12 mares at frequent intervals from 25 to 210 d of pregnancy were analyzed for equine chorionic gonadotropin (eCG). Blood and urine samples were collected daily through two consecutive ovulatory periods from five cyclic mares for comparative purposes. Separate radioimmunoassays (RIA) were developed to detect eCG in the urine and plasma. A simple and quick commercial dipstick enzyme-linked immunospecific assay (ELISA), developed for eCG in the blood, was also utilized in this study to detect eCG in the urine. In the 12 pregnant mares, eCG concentrations in both the plasma and urine as detected by RIA rose significantly on Day 40, peaked by Day 60 and slowly dropped to low levels by Day 200. The dipstick ELISA appeared more reliable for eCG in the plasma than in the urine of the five pregnant mares tested. However, on peak days (50 to 60), both the plasma and urine tested positive in all five mares. Similar eCG profiles were observed when urine samples from seven of the mares were assayed in the dipstick ELISA and RIA. The highest percentage of mares (86%) were positive for eCG by ELISA between Days 65 and 85. The highest concentration of eCG in the urine as detected by RIA was observed between Days 55 and 90. ECG-like immunoactivity was not detected by the ELISA in the urine of cyclic mares, but the RIA showed variable patterns with increases in immunoactivity that could not be correlated with physiological events. In summary, eCG in urine follows a similar profile as the eCG in plasma of mares during their first trimester of pregnancy.

Evaluation of the ability of altrenogest to control the equine estrous cycle.

In our experience, altrenogest has not always been able to exert predictable control over the estrous cycle of the mare. Therefore, we examined 12 mares that were treated with altrenogest to identify reasons for its failure to control the estrous cycle. The mares were fed altrenogest for 15 to 20 days and were examined for follicle development, ovulation, and corpus luteum formation during treatment. Through the use of real-time ultrasonography and radioimmunoassay for progesterone, we concluded that altrenogest was unable to suppress the growth of follicles to preovulatory size in some mares, leading to ovulation during treatment or earlier than expected after the end of treatment. In addition, altrenogest did not appear to shorten the life-spans of the corpora lutea that were formed during treatment; in 4 mares, this resulted in the persistence of corpora lutea after the end of the suggested 15-day periods of treatment. The latter findings led us to suggest that if a luteolytic dose of prostaglandin had been given at the end of altrenogest treatment, there would have been improved control over the estrous cycle. The results of our study confirmed our clinical impressions that altrenogest may be satisfactory to control the equine estrous cycle under some circumstances, but it should not be used when precise control over ovulation is required.

Control of the estrous cycle in the mare.

All current approaches to manipulating the reproductive biology of the nonpregnant mare are discussed.

Uterine rupture in a mare.

This report involves uterine rupture in a mare, which was unique because it was not associated with assisted or difficult foaling. We describe an alternative to surgical correction of the condition and illustrate the need for luminal uterine palpation, so that uterine rupture does not go undiagnosed.