Christine E. Hallgreen

Balancing benefit and risk of medicines: a systematic review and classification of available methodologies.

The need for formal and structured approaches for benefit–risk assessment of medicines is increasing, as is the complexity of the scientific questions addressed before making decisions on the benefit–risk balance of medicines. We systematically collected, appraised and classified available benefit–risk methodologies to facilitate and inform their future use.

Allometric Relationship between Changes of Visceral Fat and Total Fat Mass

Objective:To elucidate the mathematical relationship between changes of visceral adipose tissue (VAT) and total body fat mass (FM) during weight loss.Design:We hypothesized that changes of VAT mass are allometrically related to changes of FM, regardless of the type of weight-loss intervention, as defined by the differential equation dVAT/dFM=k × VAT/FM, where k is a dimensionless constant. We performed a systematic search of the published literature for studies that included measurements of VAT changes via magnetic resonance imaging (MRI) or computed tomography (CT) imaging along with measurements of FM changes by dual-energy X-ray absorptiometry, hydrodensitometry, air-displacement plethysmography or whole-body MRI or CT imaging. We then examined whether or not the data could be explained by the allometric model.Result:We found 37 published studies satisfying our search criteria, representing 1407 men and women of various ethnicities, degrees of adiposity and weight-loss interventions. The hypothesized allometric equation relating changes of VAT and FM accurately modeled the data for both men and women and for all methods of weight loss studied. The best-fit value for the dimensionless constant was k=1.3±0.1 and the resulting model had an R 2=0.73.Conclusion:This is the first report to reveal an allometric relationship between changes of VAT and FM that holds for both genders as well as a wide variety of weight-loss interventions including bariatric surgery, caloric restriction with or without exercise and exercise alone. We conclude that changes of VAT are primarily determined by FM changes as well as the initial VAT to FM ratio.

A Model of NEFA Dynamics with Focus on the Postprandial State

To improve the understanding of the mechanisms underlying the behavior of plasma non-esterified fatty acids (NEFA) in the postprandial state, we have developed a physiology-based mathematical model of plasma NEFA dynamics. Known physiological mechanisms are quantified and used to describe NEFA dynamics. Insulin is the major regulator of NEFA metabolism in the postprandial state. Plasma NEFA levels are thus highly dependent on the insulin concentration, the insulin sensitivity of adipose tissue, and the maximal lipolytic rate. In the postabsorptive state, e.g., at low insulin, adipose tissue lipolysis results in a net export of NEFA from adipose tissue to other tissues. Postprandially, the rise in insulin results in: Decreased lipolysis; a higher rate of lipoprotein lipase (LPL) activity; and decreased NEFA uptake and reesterification by adipose tissue stimulation of reesterification. The result is a drop in plasma NEFA after a carbohydrate containing meal. When insulin returns to postabsorptive levels, a rebound in plasma NEFA often occurs. This rebound is due to a restoration of lipolysis, a decrease in NEFA reesterification by adipose tissue and an increased LPL—as insulin activates LPL with a delay of several hours. In conclusion, movements of NEFA depend strongly on insulin—with postprandial plasma NEFA being almost inversely related to the insulin concentration in healthy humans. The model provides an integrative view of NEFA dynamics and a framework for quantitative and conceptual understanding of plasma NEFA fluxes.

Increasing weight loss attenuates the preferential loss of visceral compared with subcutaneous fat: a predicted result of an allometric model

Increasing weight loss attenuates the preferential loss of visceral compared with subcutaneous fat: a predicted result of an allometric model

Recommendations for benefit–risk assessment methodologies and visual representations

The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit–risk assessment.

Benefit-risk assessment in a post-market setting: a case study integrating real-life experience into benefit-risk methodology.

Difficulties may be encountered when undertaking a benefit–risk assessment for an older product with well‐established use but with a benefit–risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit–risk framework to assess the benefit–risk balance of warfarin for primary prevention of patients with atrial fibrillation.

A comprehensive approach to benefit-risk assessment in drug development.

Major regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit–risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data‐driven benefit–risk assessment method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval phase. The proposed benefit–risk assessment method involves eight successive steps: (1) establishment of the decision context, (2) identification of benefit and risk criteria, (3) weighting, (4) scoring, (5) evaluation of uncertainty, (6) calculation of weighted scores, (7) visualization, and (8) discussion and formulation of an overall conclusion. To reduce the impact of subjective judgements, scores are assigned to each criterion on the basis of objective information (data) wherever possible. The proposed benefit–risk evaluation approach offers comprehensive, data‐driven assessments that can facilitate decision processes. It employs descriptive statistical methods to highlight the clinically significant differences between drugs in clinical trials. The approach can be used in single as well as in multiple trials and provides clear diagrams as the basis for presentation and discussion of the results.

Literature review of visual representation of the results of benefit–risk assessments of medicinal products

The PROTECT Benefit–Risk group is dedicated to research in methods for continuous benefit–risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods.

Differences and similarities in medicine use, perceptions and sharing among adolescents in two different educational settings

Abstract Background Evidence suggests that there are differences in medicine habits among adolescents with different sociodemographic backgrounds and that peers might also influence medicine use. More knowledge is needed regarding how these aspects together affect how different young people use medicines. Objective To explore the differences in medicine use, perceptions and sharing between adolescents at two different educational (and socio-demographic) settings and assess the influence of parents and peers. Subjects Fifty-nine students from a private high school (HS) and 34 students from a public vocational school (VS) in Denmark between the ages of 15 and 19 years old were subjects in this study. Methods A questionnaire was used that included background, medicine consumption, perceptions and social interaction. Descriptive analyses along with a Fishers test were used to determine differences and similarities between students’ medicine patterns at the school settings. Results Of the 93 respondents, 74% used medicine within the past month, with females using more medicines. A significant difference was found with students at the VS using a higher number of medicines. Analgesics were the most frequently consumed medicine; however, reasons for using medicines appear to vary between the schools. Similarities between the schools were identified for perception of safety, sharing medicine and talking primarily with parents about medicine. Conclusion Fewer differences between students’ medicine use at two educational settings than expected were identified, showing that aspects other than social background influence adolescents’ use of medicine. A general tendency among young people believing that using medicines is a safe might explain these findings.