Towards consensus practices to qualify safety biomarkers for use in early drug development

Sistare, Frank D.; Dieterle, Frank; Troth, Sean P.; Holder, Daniel; Gerhold, David; Andrews-Cleavenger, Dina; Baer, William C.; Betton, Graham; Bounous, Denise I.; Carl, Kevin; Collins, Nathaniel D.; Goering, Peter L.; Goodsaid, Federico; Yi, Gu; Guilpin, Valerie B.; Harpur, Ernest S.; Hassan, Alita; Jacobson‐Kram, David; Kasper, P.; Laurie, David J.; Silva‐Lima, Beatriz; Mačiulaitis, Romaldas; Mattes, William B.; Maurer, Gerald; Obert, Leslie; Ozer, Josef; Papaluca-Amati, Marisa; Phillips, Jonathan A.; Pinches, Mark; Schipper, Matthew J.; Thompson, Karol L.; Vamvakas, Spiros; Vidal, Jean Marc; Vonderscher, Jacky; Walker, Edward A.; Webb, Craig P.; Yu, Yan

doi:10.1038/nbt.1634

Cited by 117 publications

(77 citation statements)

References 20 publications

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“…For example, the Predictive Safety Testing Consortium of the Critical Path Institute has spearheaded efforts to qualify new biomarkers of drug-induced tissue/organ injury. Seven renal safety biomarkers (kidney injury molecule-1, clusterin, albumin, total protein, ␤ 2 -microglobulin, cystatin C, and trefoil factor 3 in urine) have been qualified, outperforming or adding value to the 2 conventional biomarkers, serum creatinine and blood urea nitrogen (25 ). The FDA (in 2008), the European Medicines Agency (in 2008), and the Japanese Pharmaceuticals and Medical Devices Agency (in 2010) have issued formal regulatory opinions on the limited use of these biomarkers in nonclinical and clinical drug development to help guide safety assessments (26 ).…”

Section: Safety Biomarkersmentioning

confidence: 99%

Biomarkers in Pharmaceutical Research

Zhao

Modur²,

Carayannopoulos

et al. 2015

Clinical Chemistry

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BACKGROUND:Biomarkers are important tools in drug development and are used throughout pharmaceutical research.CONTENT: This review focuses on molecular biomarkers in drug development. It contains sections on how biomarkers are used to assess target engagement, pharmacodynamics, safety, and proof-of-concept. It also covers the use of biomarkers as surrogate end points and patient selection/companion diagnostics and provides insights into clinical biomarker discovery and biomarker development/validation with regulatory implications. To survey biomarkers used in drug development-acknowledging that many pharmaceutical development biomarkers are not published-we performed a focused PubMed search employing "biomarker" and the names of the largest pharmaceutical companies as keywords and filtering on clinical trials and publications in the last 10 years. This yielded almost 500 entries, the majority of which included disease-related (approximately 60%) or prognostic/predictive (approximately 20%) biomarkers. A notable portion (approximately 8%) included HER2 (human epidermal growth factor receptor 2) testing, highlighting the utility of biomarkers for patient selection. The remaining publications included target engagement, safety, and drug metabolism biomarkers. Oncology, cardiovascular disease, and osteoporosis were the areas with the most citations, followed by diabetes and Alzheimer disease.

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Section: Safety Biomarkersmentioning

confidence: 99%

Biomarkers in Pharmaceutical Research

Zhao

Modur²,

Carayannopoulos

et al. 2015

Clinical Chemistry

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“…Prior to the use of any new biomarker to support safety-related decisions during drug development, a substantial data set that critically assesses the analytical and biological performance of that biomarker is required. 81 Histopathological and clinical pathology evaluations are significant components in the assessment of biomarker performance. For example, the PSTC Nephrotoxicity Working Group used histopathological examination of target tissues from animal toxicology studies as the basis for the biomarker response to qualify safety biomarkers for nephrotoxicity that could outperform BUN and serum creatinine.…”

Section: Fluid Basedmentioning

confidence: 99%

Safety Biomarkers in Preclinical Development

Sasseville¹,

Mansfield²,

Brees

2013

Vet Pathol

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The identification, application, and qualification of safety biomarkers are becoming increasingly critical to successful drug discovery and development as companies are striving to develop drugs for difficult targets and for novel disease indications in a risk-adverse environment. Translational safety biomarkers that are minimally invasive and monitor drug-induced toxicity during human clinical trials are urgently needed to assess whether toxicities observed in preclinical toxicology studies are relevant to humans at therapeutic doses. The interpretation of data during the biomarker qualification phase should include careful consideration of the analytic method used, the biology, pharmacokinetic and pharmacodynamic properties of the biomarker, and the pathophysiology of the process studied. The purpose of this review is to summarize commonly employed technologies in the development of fluidand tissue-based safety biomarkers in drug discovery and development and to highlight areas of ongoing novel assay development.

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“…The standardization of histopathological diagnoses using agreed upon diagnostic lexicons is widely employed in preclinical meta-analyses (Harpur et al 2011;Sistare et al 2010). In addition, curation of histopathology data is commonly performed to consolidate diagnostic redundancies and optimize statistical evaluation through the ''binning'' of diagnoses that are analogous or represent a continuum of histopathological change (Harpur et al 2011;Vlasakova et al 2014).…”

Section: Identification and Development Of Candidate Markers Of Renalmentioning

confidence: 99%

Recent Successes in the Identification, Development, and Qualification of Translational Biomarkers

Ennulat

Adler

2014

Toxicol Pathol

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The development of novel safety or efficacy biomarkers has increasingly been used to improve safety monitoring and minimize attrition during drug development; however, for new biomarkers, the failure rate can equal or exceed that of new chemical entities. Drug-induced kidney injury is recognized to occur throughout the drug development process, with histopathology considered to be the gold standard for preclinical toxicologic screening. Renal biomarkers used clinically are primarily biomarkers of renal function and are considered insensitive for the detection of druginduced kidney injury during first-in-man studies, particularly for compounds known to induce renal injury in preclinical species. Recent efforts by public-private partnerships have led to unprecedented success in the identification, development, and qualification of several new translatable biomarkers of kidney injury in the rat. To optimize the chance of success in current and future biomarker efforts in preclinical species and man, selection and development of biomarkers should emphasize biological considerations including marker variability and biology in both health and disease. The research to support the qualification of novel renal safety markers for routine use in the clinical setting is currently underway, and results from this work are greatly anticipated.

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Towards consensus practices to qualify safety biomarkers for use in early drug development

Cited by 117 publications

References 20 publications

Biomarkers in Pharmaceutical Research

Biomarkers in Pharmaceutical Research

Safety Biomarkers in Preclinical Development

Recent Successes in the Identification, Development, and Qualification of Translational Biomarkers

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