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). 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, hyperlipidemia, 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 difficult 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 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 perturbation 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.

TABLE 4-1

Promising Translational Biomarkers of Acute Kidney Injuries.

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 nephrology and critical care, with (more...)

Key questions that need to be addressed include the following:

• Qualification of a biomarker as fit-for-purpose for safety monitoring 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 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 qualification 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 interpretation, 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 maximize the knowledge gained from such studies.
• Prospective outcome-based human clinical trials need to be conducted 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.
• 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 identification, 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 creatinine 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 measurements, 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 histopathology changes.
• Explore through further discussion whether measuring the time lag between early alterations in biomarkers and subsequent persistent 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.
• Establish the relationship among novel biomarkers, kidney damage, 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.
• 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 clinical 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 efficiently 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 industry, NIH, industry technology providers, and advocacy groups to explore the advancement of in vitro and other model systems for early drug toxicity screening.