Topic of Histopathology Blinding in Nonclinical Safety Biomarker Qualification Studies

Burkhardt, John E.; Ennulat, Daniela; Pandher, Karamjeet; Solter, Phillip F.; Troth, Sean P.; Boyce, Rogely; Zabka, Tanja S.

doi:10.1177/0192623310371221

Cited by 15 publications

(5 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The histopathology examination was conducted according to published best practices (Burkhardt et al 2010; Crissman et al 2004). A board-certified veterinary pathologist performed an initial assessment with full knowledge of the treatment groups.…”

Section: Methodsmentioning

confidence: 99%

Biomarkers of Collecting Duct Injury in Han-Wistar and Sprague-Dawley Rats Treated with N-Phenylanthranilic Acid

et al. 2012

Self Cite

View full text Add to dashboard Cite

N-phenylanthranilic acid is a chloride channel blocker that causes renal papillary necrosis in rats. Studies were conducted in two strains of male rats to evaluate novel biomarkers of nephrotoxicity. Han-Wistar rats were given daily oral doses of 50, 350, or up to 700 mg/kg/day of NPAA, and Sprague-Dawley rats were given 50 or 400 mg/kg/day of NPAA. Rats were euthanized on days 8 and 15. The candidate kidney injury biomarkers renal papillary antigen-1 (RPA-1, for collecting duct injury), clusterin (for general kidney injury), α-glutathione-S-transferase (a proximal tubular marker), and µ-glutathione-S-transferase (a distal tubular marker) were measured in urine by enzyme immunoassay. Characteristic degeneration and necrosis of the collecting duct and renal papilla were observed in Han-Wistar rats at the high dose on day 8 and at the mid and high doses on day 15, and in Sprague-Dawley rats given the high dose on days 8 and 15. Increases in urinary RPA-1, and to a lesser extent urine clusterin, were generally associated with the presence of collecting duct injury and were more sensitive than BUN and serum creatinine. On the other hand, decreases in α-glutathione-S-transferase without proximal tubule lesions in both strains and decreases in µ-glutathione-S-transferase in Sprague-Dawley rats only were not associated with morphological proximal or distal tubule abnormalities, so both were of less utility. It was concluded that RPA-1 is a new biomarker with utility in the detection of collecting duct injury in papillary necrosis in male rats.

show abstract

Section: Methodsmentioning

confidence: 99%

Biomarkers of Collecting Duct Injury in Han-Wistar and Sprague-Dawley Rats Treated with N-Phenylanthranilic Acid

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, the trial with the largest degree of observer bias 11 used a scale reported to have an intraclass correlation coefficient as high as 0.87. 40 Some researchers consider the blinding of outcome assessors too resource-demanding, superfluous, or misconceived; 41,42 however, planning and running a randomized clinical trial is already a logistically very challenging undertaking. The comparatively minor investment of using blinded outcome assessors reduces the risk of bias considerably.…”

Section: Trialmentioning

confidence: 99%

Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors

Hróbjartsson

Thomsen

Emanuelsson

et al. 2013

CMAJ

398

173

View full text Add to dashboard Cite

“…Various consortia and working groups composed of professionals from industry, academia, and government institutions have undertaken or are undertaking nonclinical work to qualify safety biomarkers of tissue injury, function, and repair. Multiple groups have been working in parallel, and participants have developed a combination of questions, answers, and opinions with regard to study execution or preferred practices to achieve study end points (Burkhardt et al 2010). Qualitative histopathology serves as a benchmark in these biomarker studies, since it is often the technique used to ultimately identify the pathologic process for which the biomarker is being developed.…”

Section: Introductionmentioning

confidence: 99%

Recommendations for the Evaluation of Pathology Data in Nonclinical Safety Biomarker Qualification Studies

et al. 2011

Self Cite

View full text Add to dashboard Cite

A set of best practices for the conduct of histopathology evaluation in nonclinical safety studies was endorsed by the Society of Toxicologic Pathology (STP) in 2004. These best practices indicate that the study pathologist should have knowledge of the treatment group and access to all available study-related data for the animal from which the tissue was obtained. A new set of best practices for the conduct of histopathology review for safety biomarker qualification for nonclinical studies has been endorsed by the STP and is summarized in this document. These best practices are generally similar to those for nonclinical safety studies, specifically that the pathologist be "unblinded" or have access to study data. Although histopathology evaluation in biomarker qualification studies must be performed without knowledge of novel biomarker data, the study pathologist(s) should be involved in the attendant meta-analyses of these data. Blinded evaluation is an experimental tool in biomarker qualification studies that is appropriate only when well-defined criteria for specific histopathologic findings are identified prior to blinded review. Additionally, this paper also considers the management of bias, the use of a tiered evaluation approach, the importance of using qualified pathologists and standard reporting, and the management of spontaneous findings.

show abstract

Topic of Histopathology Blinding in Nonclinical Safety Biomarker Qualification Studies

Cited by 15 publications

References 6 publications

Biomarkers of Collecting Duct Injury in Han-Wistar and Sprague-Dawley Rats Treated with N-Phenylanthranilic Acid

Biomarkers of Collecting Duct Injury in Han-Wistar and Sprague-Dawley Rats Treated with N-Phenylanthranilic Acid

Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors

Recommendations for the Evaluation of Pathology Data in Nonclinical Safety Biomarker Qualification Studies

Contact Info

Product

Resources

About