Accelerating the Development of Biomarkers for Drug Safety Workshop Summary (2009) / Chapter Skim
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4 Assessing and Predicting Kidney Safety
4 Assessing and Predicting Kidney Safety
Pages 29-41
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the qualification of new kidney safety biomarkers to bridge the gap between preclinical animal toxicology testing and early human clinical investigations; (2) the flawed gold standard (serum creatinine and blood urea nitrogen [BUN]
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The workshop's breakout session on kidney safety biomarkers, summarized at the end of the chapter, focused on what needs to be done to achieve this vision. THE CuRRENT STATE The current state of kidney drug development is characterized by several notable deficiencies: a limited ability to screen compounds to predict kidney toxicities; problems in identifying agents that would result in human kidney toxicity; difficulties in confirming that in some instances, kidney toxicities are specific for the tested animal species and are not necessarily relevant to humans; and a limited ability to monitor kidney damage associated with drugs that have been approved for use in humans despite their potential for nephrotoxicity because they provide health benefits or address unmet medical needs.
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Qualification of kidney Safety biomarkers As novel renal biomarkers for clinical use are developed to detect early indications of nephrotoxicity, more reliance will be placed on these biomarkers in making critical drug development decisions than is currently placed on the results of animal studies (which as noted often are not accurately predictive of human toxicity)
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, some of which involve early drug development. Many of these biomarkers could contribute unique and specific information to an overall assessment of the state of kidney function, structural perturbation of the kidneys, and the healing response.
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ASSESSING AND PREDICTING KIDNEY SAFETY BOX 4-1 Initiatives to Advance Understanding of Kidney Safety Biomarkers AKIN: The Acute Kidney Injury Network was formed in 2004 as a multidisciplinary collaborative network of members representing about 20 key societies in nephrol ogy and critical care, with additional experts in adult and pediatric acute kidney injury. AKIN has promoted the definition of acute kidney injury and has developed a research agenda to test the AKIN diagnostic and staging criteria for predicting patient outcomes in clinical settings.
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• Prospective outcome-based human clinical trials need to be con ducted to assess the relative performance of biomarkers in real time; the temporal profiles of changes in biomarkers relative to changes in renal function should be assessed by more traditional methods. • Collaboration needs to be improved across groups that have common interests in the development of kidney safety biomarkers to foster common goals and shared access to critical samples, assays, data, and funding.
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Consider the value of incorporating other measure ments, such as casts or fractional excretion of sodium, into the gold standard. • Conduct preclinical studies to explore the best fit between other laboratory variables (aside from novel renal biomarkers)
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Collaborations Among Drug Developers, Regulatory Authorities, Funding Agencies, and Investigators Many stakeholders share an interest in defining the appropriate use of new kidney safety biomarkers. An efficient approach to assessing the performance of emerging biomarkers, as well as gathering control patient data on new biomarkers, would be to add such measurements to ongoing animal and clinical trials.
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A vISION OF THE FuTuRE Table 4-2 summarizes a vision of the future for avoiding and addressing kidney safety issues in early drug development. The main features of such a vision are as follows: • In vitro test systems would be available to predict the risk of kidney toxicity, including glomerular and tubule cell injury and functional
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kidney toxicity in humans employed functional that can predict clinical measures for safety outcomes, could be used for monitoring in humans individual patient dose • Qualified kidney safety setting, and could be relied biomarkers to demonstrate on for assessing the efficacy benefits of agents directed of interventions against other diseases with • Qualified biomarkers for kidney comorbidities assessing improvements in kidney involvement as a known comorbidity of underlying disease processes changes, and to assess whether the toxicity is species-specific or is relevant to all species, including humans. • A limited number of rodent and nonrodent model systems would be available for short-term toxicology testing using a validated, easily accessible biomarker or multiple biomarkers that might include a combination of tissue and accessible biomarkers (e.g., genomic, metabolomic, protein, or imaging biomarkers)
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• Sponsors and investigators would be encouraged by regulatory authorities to demonstrate that a compound lacks the potential to injure the kidney or that kidney toxicity can be monitored and managed using qualified safety biomarkers that bridge the gap between preclinical animal studies and early human clinical trials. • Qualified predictive biomarkers for kidney toxicity in humans would be available that would outperform functional measures currently employed to predict important clinical outcomes and the efficacy of intervention strategies.
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Collection and analysis of data -- Mechanisms for accumulating • standardized preclinical data and for sharing and interpreting the data should be established through rules set by consortia. For example, assessments of histopathology need to be harmonized among the many groups working on kidney safety issues.
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2008. Monitor Monitor ing kidney safety in drug development: Emerging technologies and their implications.
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