Building Robustness into Translational Research

Erdogan, Betül R; Michel, Martin C.

doi:10.1007/164_2019_283

Cited by 12 publications

(7 citation statements)

References 59 publications

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“…Here, we present the recommendations established by the GOT-IT group, which aim to: enhance awareness of key aspects of target validation and assessment; assist in prioritizing activities for efficient use of resources; help to define project-specific value inflexion points, key activities and milestones relevant for decision-making at an early stage; and support the creation of an attractive data package as the foundation to reach the project goals. Importantly, guidance is also presented on data robustness 34 and reproducibility, thereby increasing confidence in the potential of a target and facilitating the transition from purely academic research to rigorous drug discovery. After summarizing the conceptual basis of the recommendations, this article focuses on five key areas of target assessment in which they are applied, concluding with a discussion of key issues in the application of the recommendations.…”

Section: Introductionmentioning

confidence: 99%

Improving target assessment in biomedical research: the GOT-IT recommendations

Emmerich¹,

Martínez-Gamboa

Hofmann

et al. 2020

Nat Rev Drug Discov

109

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Academic research plays a key role in identifying new drug targets, including understanding target biology and links between targets and disease states. To lead to new drugs, however, research must progress from purely academic exploration to the initiation of efforts to identify and test a drug candidate in clinical trials, which are typically conducted by the biopharma industry. This transition can be facilitated by a timely focus on target assessment aspects such as target-related safety issues, druggability and assayability, as well as the potential for target modulation to achieve differentiation from established therapies. Here, we present recommendations from the GOT-IT working group, which have been designed to support academic scientists and funders of translational research in identifying and prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical development programmes. Based on sets of guiding questions for different areas of target assessment, the GOT-IT framework is intended to stimulate academic scientists’ awareness of factors that make translational research more robust and efficient, and to facilitate academia–industry collaboration.

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Section: Introductionmentioning

confidence: 99%

Improving target assessment in biomedical research: the GOT-IT recommendations

Emmerich¹,

Martínez-Gamboa

Hofmann

et al. 2020

Nat Rev Drug Discov

109

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“…Female animals are vastly underrepresented in the literature on bladder morphology and function in diabetes ( Arioglu-Inan et al, 2018 ; Ellenbroek et al, 2018 ), which is similar to many other disease areas. Including male and female animals in every study and keeping it powered not only for the main biological comparison but also for a comparison of sexes creates challenges both on resource utilization and ethics of animal use ( Erdogan and Michel, 2020 ). Therefore, our overall research program on diabetes and the urinary bladder was designed to address this in two ways.…”

Section: Discussionmentioning

confidence: 99%

A comparison of urinary bladder weight in male and female mice across five models of diabetes and obesity

et al. 2023

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Introduction: Diabetes often leads to lower urinary tract dysfunction. The most frequently assessed parameter of urinary bladder dysfunction in animal models of diabetes is an enlargement of the bladder, which is consistently observed in type 1 and less consistently in type 2 diabetes. The vast majority of studies on bladder weight in animal models of diabetes and obesity has been performed in males, and no studies have directly compared this outcome parameter between sexes.Methods: Therefore, we have compared bladder weight and bladder/body weight ratio in five mouse models of obesity and diabetes (RIP-LCMV, db/db, ob/ob (two studies), insulin receptor substrate 2 (IRS2) knock-out mice and mice on a high-fat diet; pre-specified secondary analysis of a previously reported study).Results: In a pooled analysis of the control groups of all studies, females exhibited slightly lower glucose levels, lower body weight, and lower bladder weight, but bladder/body weight ratio was similar in both sexes (0.957 vs. 0.986 mg/g, mean difference 0.029 [−0.06; 0.118]). Among the six diabetic/obese groups, bladder/body weight ratio was similar in both sexes in three but smaller in female mice in three other groups. The mRNA expression of a panel of genes implied in the pathophysiology of bladder enlargement and/or fibrosis and inflammation did not differ systematically between sexes.Conclusions: We conclude that sex differences in diabetes/obesity-associated bladder enlargement may be model dependent.

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“…Second, human hypertension can have many causes, whereas animal models typically are mono-causal. Therefore, such animal models have benefits to identify possible pathophysiological mechanisms but may have modest translational value ( Erdogan and Michel, 2020 ). Our pathophysiological baseline data and treatment outcome findings indicate that the effect sizes presently found are most likely of insufficient magnitude to warrant implications for clinical patient management and probably too small to have implications for the clinical management of OAB or HT patients.…”

Section: Discussionmentioning

confidence: 99%

Weak association between arterial hypertension and overactive bladder baseline symptoms and treatment responses

Michel

Heemann²,

Rosette

2022

Front. Pharmacol.

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While animal studies have suggested an association between the presence of hypertension and the presence and/or severity of overactive bladder syndrome (OAB) symptoms, little clinical data is available. We have conducted a pre-specified secondary analysis of a non-interventional study involving 4450 OAB patients being treated with solifenacin to explore the existence of an association between OAB and hypertension using three parallel and overlapping definitions of hypertension to enhance robustness of analysis. Regardless of definition, patients with hypertension were older and had greater OAB symptom severity in univariate analyses. In multiple regression models including age as explanatory covariate, most relationships held up but effect sizes of concomitant hypertension on OAB severity were small (odds ratios <1.35 in all cases) and were deemed to be unlikely of clinical relevance. % Changes in symptom severity were somewhat smaller in univariate analysis, but effect sizes were small. We conclude that OAB and arterial hypertension are associated but effect sizes are too small to justify adaptation of clinical practice for OAB patients with concomitant hypertension.

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Building Robustness into Translational Research

Cited by 12 publications

References 59 publications

Improving target assessment in biomedical research: the GOT-IT recommendations

Improving target assessment in biomedical research: the GOT-IT recommendations

A comparison of urinary bladder weight in male and female mice across five models of diabetes and obesity

Weak association between arterial hypertension and overactive bladder baseline symptoms and treatment responses

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