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4
Assessing and Predicting Kidney Safety1
One of the primary reasons for the attrition of promising therapeutic
agents from the drug development pipeline is the observation of treatment-
related histologic injury to the kidney in animal toxicology studies. At
the same time, the ability to recognize when a therapeutic intervention is
damaging the kidneys in humans and to predict when removal of that agent
would arrest further deterioration is severely limited. Progress in identify-
ing, evaluating, and qualifying biomarkers of kidney injury would therefore
yield great benefits in drug development.
This chapter describes the current state of biomarker use and devel-
opment in four specific areas: (1) 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]) that plagues the assessment of
new kidney safety biomarkers; (3) collaborations among drug developers,
regulatory authorities, funding agencies, and investigators; and (4) the
development of in vitro and other screening model systems that could
identify lead candidates for drug development. In each of these areas, the
major questions that need to be answered and the hurdles that need to be
1 This chapter is derived from a white paper prepared by Frank D. Sistare, Merck & Co.,
Inc., and Prasad Devarajan, Cincinnati Children’s Hospital Medical Center, University of
Cincinnati, with additional input from workshop discussions. Panelists contributing to the
paper were Joseph Bonventre, Harvard Medical School, Brigham and Women’s Hospital;
Frank Dieterle, Novartis Pharma; Robert Star, National Institute of Diabetes Digestive and
Kidney Diseases, NIH; and David Warnock, University of Alabama at Birmingham. Melanie
Blank, FDA, participated in the panel.
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0 DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
overcome are presented. The chapter then describes a vision for the future
development and use of kidney safety biomarkers in drug development. 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 sev-
eral 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 associ-
ated 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. Current approaches to toxicity testing and decision
making can waste time and resources and may not identify or support
development of the best lead candidates for human use.
The kidney is a major site of drug metabolism and elimination, so
it is not surprising that toxicologic findings are more common in the
kidney than in most other organs. Merck has reported that renal injury
is the second-leading cause of drug attrition, after liver toxicity (Merck,
unpublished findings). Indeed, commercially marketed drugs with known
nephrotoxic potential are contributing factors in at least 25 percent of
acute kidney injury in critically ill humans, causing significant increases in
mortality, morbidity, and health care costs (Pannu and Nadim, 2008).
As noted, the current biomarker gold standard for kidney toxicity is
levels of serum creatinine and BUN. These measures of kidney function are
not sensitive indicators of structural injury, however, in part because of the
excess capacity—or “renal reserve”—of the kidneys (Ferguson et al., 2008;
Parikh and Devarajan, 2008). In the absence of more sensitive biomarkers
to detect acute changes in renal damage, early indications of kidney injury
cannot be monitored without histologic examination.
Histology provides accurate detection of kidney injury in preclinical
animal studies. However, the current standard of care for evaluation of
potentially nephrotoxic agents in human studies does not extend to surveil-
lance with renal biopsies. As a result of this inability to monitor for early
indications of kidney injury in human subjects, the development of com-
pounds found to cause kidney damage in preclinical animal studies may be
suspended, even when the relevance of the findings to humans has not been
established. Drug toxicities seen in animal studies account for more than
30 percent of the attrition of compounds from drug development (Kola and
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ASSESSING AND PREDICTING KIDNEY SAFETY
Landis, 2004). It is important to note that adverse findings from one species
in animal toxicology studies are not always seen in other species, and only
40 to 60 percent of such findings are predictive of toxicities in human
trials (Olson et al., 2000; Knight, 2008). Thus, promising compounds are
dropped from the development pipeline even though adverse kidney effects
in humans might not ever occur or might be manageable through monitor-
ing with sensitive biomarker tests.
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 accu-
rately predictive of human toxicity). It may be hoped that this will both
improve the safety of drugs and decrease the need to conduct exhaustive
preclinical studies (Sistare and DeGeorge, 2007).
Novel renal biomarkers may also ultimately play a role as surrogate
markers of drug efficacy. Many companies are working to develop new
drugs for treating diabetes, hypertension, obesity, heart failure, hyper-
lipidemia, and transplant rejection, conditions in which the possibility of
kidney injury is an ever-present risk. Since current biomarkers of kidney
injury and function lack sensitivity and specificity, it is difficult to properly
assess kidney status at baseline or after treatment. New drugs might actually
be ameliorating or slowing the progression of kidney diseases, but without
sensitive and specific measures of clinically meaningful renal injury and/or
function, improvements during treatment of these diseases is extremely dif-
ficult to assess. At this time, improvements in renal function can be assessed
only by conducting large and lengthy clinical trials (using doubling of serum
creatinine as the efficacy endpoint). Once it has been established that novel
renal biomarkers are predictive of future renal morbidity, they will likely be
accepted as surrogate markers of clinically meaningful renal disease and be
relied upon to assess renal benefits during drug development.
Biomarkers have already been developed as surrogates in other areas.
For example, large-scale trials have shown that statins reduce the risk of
adverse cardiovascular outcomes, and the reduction they cause in serum low-
density lipoprotein (LDL) levels is predictive of this effect. LDL cholesterol
is now accepted as a surrogate endpoint for regulatory marketing approval.
But examples of such biomarkers remain rare, and the burden of proof for
marketing approval is high.
Table 4-1 lists several promising translational biomarkers of acute
kidney injury that have been proposed in published studies (Dieterle et al.,
2008; Ferguson et al., 2008; Parikh and Devarajan, 2008). A number of
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
TAbLE 4-1 Promising Translational Biomarkers of Acute Kidney Injuries
Urinary or Serum
Biomarker Proposed Structural/Functional Interpretations
Urine Albumin Biomarker for glomerular and tubular epithelium functional change
Urine α-GST Tubular epithelium cell membrane disruption and cytosol leakage
Urine KIM-1 Proximal tubule epithelium dedifferentiation and regenerative repair
response
Urine NGAL Distal tubule and collecting duct rescue signal to bind deleterious
substances, limit damage, and promote survival and proliferation
Urine TFF3 Decrease in concentration removes cellular maturation signaling,
allowing dedifferentiation
Serum Cystatin C Functional measure of glomerular filtration
Urine Cystatin C Biomarker for glomerular alterations or tubular damage that
interferes with efficient proximal tubular protein reabsorption
Urine Biomarker for glomerular alterations or tubular damage that
β2-Microglobulin interferes with efficient proximal tubular protein reabsorption
Urine Protein Biomarker for glomerular and tubular epithelium functional change
Urine L-FABP Biomarker of anoxia/ischemia signal in tubular epithelium and
potential oxidative damage signal
Urine Clusterin Biomarker for tubular epithelium regenerative repair response
Urine NAG Biomarker for proximal tubule lysosomal enzyme release and
proximal tubular damage
Urine IL-18 Tubular epithelium protein reflecting initiation of apoptotic
cascades
Urine GGT Tubular epithelium cell membrane disruption
NOTE: α-GST = glutathione-s-transferase alpha; KIM-1 = kidney injury molecule-1; NGAL =
neutrophil gelatinase associated lipocalin; TFF3 = trefoil factor-3; L-FABP = liver type fatty
acid binding protein; NAG = n-acetyl glucosaminadase; IL-18 = interleukin-18; GGT = gamma
glutamyl transferase.
groups are collaborating to advance understanding of these biomarkers
for specific uses (Box 4-1), 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 perturba-
tion of the kidneys, and the healing response. A prospectively defined and
systematically collected data set could allow some of these biomarkers to
gain broad acceptance and qualification for monitoring renal safety in early
clinical human registration trials.
Key questions that need to be addressed include the following:
• Qualification of a biomarker as fit-for-purpose for safety monitor-
ing is an antecedent to qualification of that biomarker as fit-for-
purpose for an efficacy outcome. Some biomarkers may be ideally
suited to safety monitoring and early detection of kidney injury but
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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.
C-Path PSTC NWG: The Critical Path Institute’s Predictive Safety Testing Con-
sortium Nephrotoxicity Working Group was formed in 2006. It includes repre-
sentatives of 16 companies working with academic advisors, the FDA, and the
European Medicines Evaluation Agency (EMEA) to establish and qualify trans-
lational bridging biomarkers for use in monitoring drug-induced kidney injury for
regulatory decision-making purposes in both animal toxicology studies and early
clinical trials.
ILSI/HESI Kidney Biomarker Committee: The Kidney Biomarker Committee
of the International Life Sciences Institute/Health and Environmental Sciences
Institute consists of 10 companies collaborating to evaluate promising accessible
biomarkers of drug-induced kidney toxicity in animals.
IMI: The Innovative Medicines Initiative is a European-based public–private
partnership between the pharmaceutical industry, represented by the European
Federation of Pharmaceutical Industries and Associations, and the European Com-
munities, represented by the European Commission. Its goal is to remove research
bottlenecks in the current drug development process. The first round of projects,
which start in 2009, includes one consortium that is investigating mechanisms of
drug-induced hepatotoxicity and nephrotoxicity and defining safety biomarkers in
different animal species, and a second consortium aimed at the clinical qualifica-
tion of safety biomarkers for monitoring drug-induced kidney, liver, and vascular
injury in humans.
Extramural NIH Studies: Examples include the Acute Kidney Injury Natural
History Cohort consortium, the Translational Research Investigating Biomarker
Endpoints in Acute Kidney Injury (TRIBE-AKI) consortium, the University of
A
labama-Birmingham/University of California-San Diego O’Brien Kidney Research
Core Center, the Chronic Kidney Disease Biomarkers Consortium, and the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Workshop on
Assessment of Kidney Function and Damage. Academic biomarker development
projects include those at Harvard University, the University of Cincinnati, and the
University of Colorado.
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
may not be appropriate as surrogate endpoints of clinical efficacy.
Which data are critical for establishing that a specific biomarker is
fit-for-purpose (Wagner et al., 2007)?
• How can existing data sets from animal and human studies be used
most effectively to support qualification of safety biomarkers?
• How can diverse stakeholders best collaborate and set reasonable
expectations and evidentiary standards for fit-for-purpose qualifica-
tion of candidate safety biomarkers and generate any needed new
data?
• How can the decision-making processes be made transparent to all
stakeholders?
There are a number of opportunities for answering these questions:
• Biomarkers that appear to outperform changes in serum creatinine
measurements in animal toxicology studies need to be identified, and
a harmonized lexicon needs to be established for histopathology as
the gold standard for these preclinical studies.
• A critical review of published studies needs to be conducted to
identify the most promising new renal biomarkers. If possible,
data from these studies should be collected into a usable shared
database.
• Standardized methodologies need to be used for preclinical and
clinical data collection, sample collection, histopathology interpre-
tation, biomarker measurements, and data interpretation. These
methodologies should reflect the collaborative efforts of experts
and vested stakeholders, including sponsors, investigators, and
regulatory scientists.
• Biomarker studies are needed to better understand such biological
processes as the anatomical region and cell types perturbed in kidney
injuries, the functions perturbed, and the recovery response.
• Tissue sample and biomarker banks need to be created. The use of
both fresh samples and archived, frozen, or formalin-fixed samples
should be optimized to minimize the drain on resources and maxi-
mize the knowledge gained from such studies.
• 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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ASSESSING AND PREDICTING KIDNEY SAFETY
• Funding needs to be optimized through partnering with NIH.
• Biomarker thresholds need to be established. Normal ranges based
on variance and intervention thresholds need to be determined
based on medical experiences with a variety of study populations.
• The output from diverse work streams needs to be directed to key
regulatory decision and policy makers at the same time that drug
developers are kept fully informed through written communications
and regular meetings that include all interested stakeholders.
• Issues surrounding the commercial development of biomarker assay
panels for use in human and animal studies need to be considered,
including technical and fiscal issues surrounding the identifica-
tion, validation, commercial development, and acceptance of multi-
marker panels.
The Flawed Gold Standard
When comparing the sensitivity and specificity of two or more tests,
it is important to have a standard against which to make the comparison.
Otherwise, one can see only how two measures correlate with one another,
and comparison of the sensitivity and specificity of new biomarkers to cre-
atinine or other more traditional biomarkers of kidney function and injury
in the clinical setting is difficult. For ethical reasons, kidney biopsy—which
would be an ideal standard for assessment of the performance of new
biomarkers when nephrotoxicity is suspected in the clinical setting—is not
possible. Unfortunately, as discussed above, the current gold standard of
serum creatinine and BUN is seriously flawed.
There are several major research opportunities for developing an
improved standard:
• Conduct studies to explore the utility of adjudication committees
or more complex algorithms of renal dysfunction as better gold
standards. 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) and histo-
pathology changes.
• Explore through further discussion whether measuring the time
lag between early alterations in biomarkers and subsequent per-
sistent serum creatinine elevations and/or other traditionally used
biomarker changes (perhaps in a patient population with no renal
reserve) might be an adequate way to qualify renal biomarkers for
use in Phase 1 clinical trials.
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
• Establish the relationship among novel biomarkers, kidney dam-
age, and serum creatinine by analyzing ongoing studies in which
human biopsy samples are available. Examples include protocol
transplant biopsies and biopsies of patients with hematuria or
proteinuria in whom serum creatinine may still be normal despite
kidney injury as reflected by histopathology.
While the initial focus must necessarily be on safety monitoring, the
ultimate application of these endpoint considerations to efficacy trials
should be kept in mind. To this end, it will be necessary to establish
the relationships between biomarker elevation and appropriate short-,
intermediate-, and long-term clinical outcome measures, such as dialysis,
death, and hospitalization days; repeated hospitalization, infections, or
resource utilization; or progression to chronic kidney disease, end-stage
renal disease, or cardiovascular disease.
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. However, there currently are few incentives and
many disincentives to adding measurements from unqualified exploratory
safety biomarkers to such regulated studies (Sistare and DeGeorge, 2008).
Key questions that must be addressed include the following:
• How can regulatory authorities establish and communicate an
official regulatory policy to support the innovative development of
safety biomarkers within the context of product development?
• Can regulatory authorities provide encouragement or support to
advance the evaluation of a declared set of safety biomarkers using
samples from ongoing registration studies?
• Can other, nonregulatory federal agencies provide access to samples
from clinical trial sample sets that would allow a prioritized list of
new safety biomarkers to be developed?
Major opportunities exist for answering these questions:
• Transparent and realistic communications need to occur between
regulatory authorities and drug development scientists.
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ASSESSING AND PREDICTING KIDNEY SAFETY
• Disincentives under the current drug development framework need
to be removed.
• Issues of patient consent in clinical trials pertaining to testing of
novel biomarkers need to be resolved.
• Exploratory studies and studies of negative controls are needed.
• A role for NIH-sponsored clinical natural history studies and clini-
cal trials in this overall process needs to be identified.
• Roles for public–private partnerships and patient advocacy groups
need to be identified.
• FDA–industry–NIH partnerships for monitoring drug safety and
toxicity and providing broad access to study samples need to be
explored.
Development of in vitro and Other Screening Model Systems
In vitro and other screening model systems that could definitively rule
out human kidney toxicity caused by test compounds and identify specific
kidney toxicities in animal test species would be exceedingly helpful in drug
development. Key questions in this area include the following:
• Are such systems viable and close to being established?
• How can their evolution be fostered, and how can they be effi-
ciently validated?
There are several major opportunities for answering these questions:
• Studying the role and limitations of current primary cell cultures
and of embryonic stem cells for assessing new biomarkers.
• Studying the utility of other in vitro model systems of nephrotoxicity
(e.g., in zebrafish).
• Creating partnerships among academia, the pharmaceutical indus-
try, NIH, industry technology providers, and advocacy groups to
explore the advancement of in vitro and other model systems for
early drug toxicity screening.
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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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
TAbLE 4-2 Current Deficiencies, Needs, and Proposals to Address
Kidney Safety Issues in Early Drug Development
Concept Current Needs Future Availability
Improved kidney injury • Qualified biomarkers and • In vitro and other screening
biomarkers and kidney screening test systems for model systems that can
toxicity screening identifying human-relevant predict kidney toxicity,
systems would help kidney toxicities injury, and functional
optimize the selection of • Qualified biomarkers to changes in preclinical and
leading candidates for monitor kidney toxicity in clinical studies
development and animals noninvasively • Expedited resource-sparing
provide for better drug study designs incorporating
development animal readily available
toxicology studies. commercial multiplexed
assays and tissue
biomarkers that report/
predict kidney toxicity in
animals
Biomarkers that enable • Qualified biomarkers of • Translational qualified
early detection and acute kidney toxicity to biomarkers for monitoring
monitoring of toxicity translate from animals to kidney safety in animal
and structural and humans that outperform toxicology studies and
functional changes in currently employed early human clinical trials
humans would enable functional measures • Translational qualified
safety monitoring of • Once safety biomarkers predictive biomarkers for
both early and later have been established, kidney toxicity in humans
phases of clinical drug qualified biomarkers for that outperform currently
development. 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). These biomarkers
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ASSESSING AND PREDICTING KIDNEY SAFETY
would predict dose-dependent acute kidney injury in terms of dys-
function, anatomic alteration, or structural damage.
• Readily available qualified human biomarkers would be avail-
able to diagnose or rule out the involvement of specific anatomic
regions, to assess the severity of an injury, to signal the need
for early intervention, and to monitor the reversibility of injury-
associated processes.
• 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. These biomarkers would be
defined according to their applicability to patients with chronic
kidney disease, as well as those with no known kidney disease.
• Where kidney involvement is a known comorbidity of disease,
qualified biomarkers would be available to assess the effects of a
drug on kidney processes in Phase II and III trials.
• Qualified biomarkers for kidney injuries would be used to diag-
nose and stage kidney diseases with pathologies related to kidney
toxicities.
HIGHLIGHTS OF THE bREAkOuT DISCuSSION
The breakout group that discussed biomarkers for kidney toxicity
focused on prioritizing what needs to be done to achieve the future vision
outlined above. Participants discussed the most critical obstacles and data
gaps that need to be addressed in the four areas reviewed in the above
section on the current state of renal biomarker development. In the ple-
nary session following the breakout, Prasad Devarajan of the Cincinnati
Children’s Hospital Medical Center, University of Cincinnati, presented the
group’s main conclusions:
Greater understanding of biomarkers—The group concluded that
•
new biomarkers should outperform those already available. The
current gold standard for preclinical biomarker discovery is animal
toxicity studies based on histopathology, and the use of that stan-
dard should continue. Also needed are biomarkers that indicate
the anatomic site of kidney injury in animal studies because differ-
ent agents can affect different nephron segments, and biomarkers
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0 DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
should provide temporally ordered information regarding the stage
of kidney injury. Needed as well is greater understanding of what
biomarker combinations reveal about the stage of kidney injury or
repair.
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. Because
data on long-term clinical outcomes can take many years to
gather, it is important that short-term outcomes—including serum
creatinine, dialysis requirements, and mortality—be correlated with
biomarkers.
Correlations with biopsies—Efforts should be made to correlate
•
human biopsy histopathology with biomarkers. While not all
patients with nephrotoxicity are biopsied, more can be learned from
the biopsies that are being done, such as the protocol kidney trans-
plant biopsies that are frequently performed in many institutions.
Biopsies of patients with blood in the urine and glomerular disease
should be simultaneously correlated with noninvasive biomarkers.
National biorepositories—Standardized national biorepositories need
•
to be established to enable comparison of biomarkers from ongo-
ing clinical trials. Researchers should have access to de-identified
samples, and it should be possible to share data generated from
these samples. NIH has a public–private partnership office that could
coordinate this cooperation. In addition, a system is needed for shar-
ing clinical data, including data gathered by industry.
Incentives, dialogue, and partnerships—Incentives could be struc-
•
tured to promote investigations of new safety biomarkers in regu-
lated studies that support new product development. Incentives also
need to be considered for exploratory studies and negative controls.
An open dialogue between industry and regulatory agencies could
identify and refine such incentives. In addition, an FDA–NIH part-
nership could consider funding research on biomarker development
for monitoring drug safety and toxicity, making the FDA a funding
as well as a regulatory agency.
Preclinical model systems—In vitro and other screening models
•
need to be developed for detecting nephrotoxicity. Clinical and
animal studies are expensive. Cell culture systems have not been
very reliable, but new systems, such as embryonic stem cells and
zebrafish models, are promising, and additional models may
emerge. A partnership between industry and NIH could accelerate
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ASSESSING AND PREDICTING KIDNEY SAFETY
the development of these in vitro and other systems for detecting a
compound’s nephrotoxicity potential.
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