Predictive Safety Testing Consortium

The US Food and Drug Administration (FDA) issued its first ever qualification of a clinical safety biomarker based on data submitted jointly by the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium (BC) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium (PSTC).

The qualification applies to a single composite measure (CM) of six urine biomarkers, to be used in conjunction with traditional measures of kidney function; the six safety biomarkers include clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN).

• FDA Qualification Letter (August 15, 2018)

The purpose and Context of Use (COU) for this qualified biomarker are as follows: A safety composite biomarker panel to be used in conjunction with traditional measures to aid in the detection of kidney tubular injury in phase 1 trials in healthy volunteers when there is an a priori concern that a drug may cause renal tubular injury in humans.

Use of the CM biomarker will help improve the development of safe and effective medicines where concern has been raised that an investigational drug may cause kidney injury. As stated in the FDA’s Qualification Decision and Executive Summary, “This biomarker can be used by drug developers for the qualified COU in submissions of investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs) without the need to resubmit the biomarker information or rereview by the relevant [Center for Drug Evaluation and Research] CDER disciplines.”

The CM is qualified as a safety biomarker for dose cohorts, not for individual patient/study subject monitoring.

Using the CM in Phase 1 clinical trials (with healthy volunteers as subjects) in conjunction with standard measures of renal function (serum creatinine [sCr], blood urea nitrogen [BUN], urine albumin, and urine total protein) can help clinicians and investigators monitor the risk of renal tubular injury and may inform subsequent decision-making in the drug development process.

Additional details are available in the User’s Guide: Kidney Safety Composite Measure Biomarker for Use in Clinical Development.

Decision tree for clinical use of qualified CM biomarker in a Phase 1 trial involving healthy human subjects

Included with the qualification determination are important considerations and sensible practices related to use of the CM; these are outlined in the FDA’s Qualification Decision and Executive Summary.

Additional details regarding this biomarker qualification, including specific information about how it can be used in drug development programs and clinical trials, are available on the FDA’s Biomarker Qualification Program website.

Following several years of PSTC’s collaborative research, the FDA, European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) have each qualified seven novel laboratory tests on urine which signal kidney injury. The safety biomarkers were evaluated in data from rat studies submitted to the regulatory agencies by PSTC. The qualified biomarkers are kidney injury molecule-1, albumin, total protein, β2-microglobulin, cystatin C, clusterin, and trefoil factor-3.

• FDA Qualification Statement (April 4, 2008)
• EMA Qualification Statement (May 23, 2008)
• PMDA Qualification Statement (May 31, 2010)

These tests can be used in laboratory research to predict the safety of experimental drugs. The details of this research and qualification are available in these articles:

http://www.ncbi.nlm.nih.gov/sites/myncbi/collections/public/1h9C-otw1T5zb8Ra6o0EUYzkG/

The FDA has issued a Letter of Support to the Predictive Safety Testing Consortium (PSTC) to encourage the further study and use of a set of translational safety biomarkers to detect and monitor drug-induced pancreatic injury (DIPI). The set of biomarkers are four micro RNAs (miRNAs) under investigation for DIPI are miR-216a, miR-216b, miR-217, and miR-375.

The translational pancreatic safety biomarkers (miR-216a, miR-216b, miR-217, and miR-375) will be used in conjunction with amylase and lipase to aid in the detection of DIPI in Phase 1 clinical trials when there is demonstrated monitorability of induced damage in nonclinical studies and sufficient safety margins or when there is a priori concern that a drug candidate may induce DIPI due to known structural class similarities or identified target liability concerns.

Novel biomarkers of DIPI used in combination with currently available biomarkers could play an important role in guiding safety assessment in phase I clinical trials. Although the standard markers of pancreas injury, amylase and lipase, are currently the clinically accepted biomarkers for the diagnosis of acute pancreatitis (IAP/APA evidence-based guidelines for the management of acute pancreatitis, 2013), it is widely acknowledged that they are not sufficiently sensitive nor specific to guide dosing-related decisions in clinical trials (Lee and Papachristou, 2019; Ismail and Bhayana, 2017).

We support PSTC’s initiative to encourage the voluntary and complementary use of these miRNAs in conjunction with amylase and lipase as exploratory nonclinical and clinical biomarkers of DIPI. We also support PSTC’s generation of additional nonclinical toxicology data and plan for exploratory early clinical studies to enable future formal qualification of these safety biomarkers.

MiRNA molecules are short non-coding sequences ranging from 19 to 25 nucleotides in length, which are involved mainly in the post-transcriptional modulation of gene expression. A diverse array of functions including cellular signaling, cell growth and differentiation and apoptosis have been described for miRNAs. In humans, approximately 2,600 miRNA genes are currently known. Information on miRNA identification and nomenclature can be found at www.mirbase.org. Because of the relative abundance of miRNAs in specific tissues, they are increasingly being recognized as leakage biomarkers indicative of tissue injury (Bailey and Glaab, 2018; Schraml et al., 2017). A number of candidate miRNAs have been identified and studied in association with pancreatic acinar injury in nonclinical species (Erdos, 2020; Usborne, 2014), including miR-217, miR-216a, miR-216b, and miR-375.

Member companies of the PSTC PIWG have conducted studies and assessed pancreas-specific miRNAs to determine their performance in monitoring drug-induced toxicities. Toxicants targeting Exocrine/Acinar Predominant Injury (caerulein, caerulein perfusion, cholecystokinin, L-arginine, cyanohydroxybutene, DL-Ethionine, sodium taurocholate, Dibutyltin dichloride, Ethanol + Cyclosporin A + caerulein, ductal retrograde trinitrobenzene sulfonic acid, and proprietary drug candidates) and Endocrine/Islet Predominant Injury (streptozotocin and proprietary drug candidates) assessed the performance of the miRNAs to detect DIPI in rats (all toxicants) and dog (only cholecystokinin). The studies supporting this Letter of Support were published in peerreviewed scientific journals. These pancreas-specific miRNAs have been evaluated as biomarkers of DIPI and show promise to add value to the interpretation of amylase and lipase in monitoring acute pancreatic injury defined as acinar cell degeneration/necrosis.

More experience with the use of this biomarker in clinical studies would be useful to determine its utility more accurately for detecting and monitoring drug-induced pancreatic injury. MicroRNA thresholds have yet to be determined in clinical samples. Assessment will be in conjunction with amylase and lipase and not be used independently for decision making. Future studies will determine the clinical thresholds and the interpretation of results including performance metrics. We encourage exploration of these miRNAs (miR-217, miR-216a, miR-216b, and miR-375) used, in conjunction with amylase and lipase, to aid in the detection of DIPI in Phase 1 clinical trials when there is demonstrated monitorability of induced damage in nonclinical studies and sufficient safety margins or when there is a prior concern that a drug candidate may induce DIPI due to known structural class similarities or identified target liability concerns.

Any groups (academia, industry, government) that would like to join in this effort or have information or data that may be useful can contact Mr. Nicholas King (nking@c-path.org) or view the PSTC website.

The U.S. Food and Drug Administration (FDA) and European Medicines Agency, recently, issued Biomarker Letters of Support (LOS) for the skeletal muscle injury safety biomarkers myosin light chain 3 (Myl3) and skeletal muscle troponin I (sTnI), fatty acid binding protein 3 (Fabp3), and creatine kinase M (CK-M) based on data submitted by the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Skeletal Myopathy Working Group (SKMWG). These letters briefly describe the U.S. FDA’s and EMA’s thoughts on the value of Myl3, sTnI, Fabp3, and Ckm and encourage further evaluation of biomarkers with promising utility in drug development.

• FDA Letter of Support (January 22, 2015)
• EMA Letter of Support (March 6, 2015)

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA for the regulatory decision on use of serum/plasma Myl3, sTnI, Fabp3, and Ckm in nonclinical and exploratory clinical studies.

Decision tree for translational use of Myl3, sTnI, FABP3, and CK-M in a drug development program

Following the determination that Myl3, sTnI, Fabp3, and Ckm can add value to conventional biomarkers for monitoring skeletal muscle degeneration/necrosis in a prospective rat GLP study, sponsors are encouraged to discuss proposals for use of human Myl3, sTnI, Fabp3, and Ckm to enable the safe conduct of clinical studies with the appropriate regulatory review body.

The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), recently, issued Biomarker Letters of Support (LOS) for the drug-induced vascular injury safety biomarkers for the following: endothelial cell proteins (E‐Selectin, P‐Selectin, sICAM‐1, sICAM‐3, sVCAM‐1, thrombomodulin, and VEGF); smooth muscle cell proteins (EMA only: calponin, caldesmon); and inflammatory factors (CRP, GROa, NGAL, IL‐6, IL‐8, IP‐10, I‐TAC, MCP‐1, MIG, SAA, MIP‐1α, and TIMP-1) based on data submitted by the Innovative Medicine Initiative’s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Vascular Injury Working Group (VIWG).

• FDA Letter of Support (November 7, 2016)
• EMA Letter of Support (November 7, 2017)

These letters, describe the U.S. FDA’s and EMA’s thoughts on the value of the DIVI biomarkers and encourages further evaluation. The EMA’s LOS encourages “further nonclinical and exploratory clinical analyses to evaluate the translational relevance of changes in identified nonclinical DIVI biomarkers.” The FDA’s LOS encourages “additional use of these biomarkers to characterize their potential role for monitoring DIVI in early clinical drug development.”

Although not qualified by FDA or EMA, these translatable biomarkers, alone or in panel(s), are anticipated to reflect DIVI affecting vascular smooth muscle cells and endothelial cells, as well as the associated inflammatory response, as determined by histopathologic endpoints in rodents. It is envisioned that the vascular injury biomarkers will ultimately be used in healthy volunteers with no concurrent vascular disease to monitor for vascular safety in early clinical trials. These biomarkers will be used when such injury has been demonstrated to be monitorable by translatable biomarkers in animal studies of similar duration with the same test agent (including small and large molecule therapeutics). Applying the biomarkers in initial single and multiple ascending dose clinical studies could help inform planned dose escalations or continued dosing schedules.

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA for the regulatory decision on use of the DIVI biomarkers in nonclinical and exploratory clinical studies.

The U.S. Food and Drug Administration (FDA) and European Medicines Agency, recently, issued Biomarker Letters of Support (LOS) for the kidney safety biomarkers osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) based on data submitted by the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Nephrotoxicity Working Group (NWG). The Summary Data Package reports the relationship between kidney proximal tubule degeneration/necrosis and urinary levels of OPN and NGAL in rodents. These letters briefly describe the U.S. FDA’s and EMA’s thoughts on the value of urinary OPN and NGAL and encourage further evaluation of biomarkers with promising utility in drug development.

• FDA Letter of Support (August 20, 2014)
• EMA Letter of Support (November 6, 2014)

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA for the regulatory decision on use of urinary OPN and NGAL in nonclinical and exploratory clinical studies.

Decision tree for translational use of urinary OPN and NGAL in a drug development program

Following the determination that OPN and NGAL can add value to conventional biomarkers for monitoring kidney tubular degeneration/necrosis in a prospective rat GLP study, sponsors are encouraged to discuss proposals for use of human urinary OPN and NGAL to enable the safe conduct of clinical studies with the appropriate regulatory review body.

The European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) have both issued separate Letters of Support (LOS) to encourage the further development and exploratory use of percent change from baseline of the following urinary markers: alpha-glutathione S-transferase (α-GST), clusterin (CLU), cystatin C (CysC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), albumin (ALB) and total protein (TPRO) as biomarkers of drug-induced renal tubular injury in early clinical trials. The EMA also supports the use of serum cystatin C utilizing the percent change from baseline approach proposed by the DIKI group. These Letters of Support are based on data submitted by the Innovative Medicine Initiative’s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Nephrotoxicity Working Group (HWG).

• FDA Letter of Support (November 23, 2016)
• EMA Letter of Support (December 14, 2016)

These letters describe FDA’s and EMA’s thoughts on the value of α-GST, CLU, CysC, KIM-1, NGAL, OPN, ALB and TPRO and encourages further evaluation. The FDA’s LOS encourages “the exploratory use of these urinary biomarkers (α-GST, CLU, CysC, KIM-1, NGAL, OPN, ALB, and TPRO) as biomarkers of renal tubule injury in early clinical trials.”

Additionally, the FDA stated that the “exploratory human data suggests that the candidate drug-induced renal tubular injury biomarkers may be more sensitive and specific for the detection of acute kidney injury, especially when used in combination, than traditional means of monitoring for nephrotoxicity. In addition, you observed a rise in most of the candidate biomarkers (urinary a-GST, CLU, KIM-1, NGAL, CysC, and OPN) that preceded a clinically-relevant rise in sCr.”

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA.

The European Medicines Agency (EMA), recently, issued a Biomarker LOS,  for the drug-induced liver injury safety biomarkers Glutamate Dehydrogenase (GLDH) based on data submitted by the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Hepatotoxicity Working Group (HWG) and the Duchenne Regulatory Science Consortium (D-RSC).

• EMA Letter of Support (November 27, 2017)

This letter briefly describes EMA’s thoughts on the value of GLDH and encourages further evaluation. The EMA’s LOS supports “PSTC’s and D-RSC’s initiative to encourage investigation of the voluntary and complementary use of serum GLDH, in conjunction with currently used biomarkers of liver injury, as a clinical biomarker of liver injury. The Agency also supports PSTC’s generation of additional clinical safety data and plans for further clinical studies to potentially enable formal qualification of GLDH in the future.”

The U.S. Food and Drug Administration (FDA) issued Biomarker Letters of Support for the drug-induced liver injury safety biomarkers Cytokeratin 18 (CK-18), Total and hyperacetylated high mobility group protein B1 (HMGB1), Osteopontin, and Macrophage colony-stimulating factor 1 receptor (CSF1R) based on data submitted by the Innovative Medicine Initiative’s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Hepatotoxicity Working Group (HWG).

• FDA Letter of Support (July 25, 2016)

This letter briefly describes U.S. FDA’s thoughts on the value of CK-18, HMGB1, Osteopontin, and CSF1R and encourages further evaluation. The U.S. FDA’s LOS encourages further evaluation of biomarkers with promising utility in drug development either “alone or in combination as soluble monitoring biomarkers to assess the risk of progression of drug-induced liver injury (DILI) in patients in whom an initial DILI diagnosis has been established based on elevations of the standard biomarkers alanine aminotransferase (ALT) alone or in combination with total bilirubin (TBIL) as a clinical safety assessment in clinical trials in a drug development context.”

• Summary Data Package

In concert with C-Path’s Duchenne Regulatory Science Consortium, on November 8, 2019 PSTC submitted a Letter of Intent (LOI) to the U.S Food and Drug Administration (FDA) for a panel of four novel safety biomarkers of acute drug-induced muscle injury (DIMI) in phase I clinical trials with healthy volunteers. The LOI received a positive response and has been accepted into FDA’s Center for Drug Evaluation and Research (CDER) Biomarker Qualification Program (BQP).

Click here to read the press release and view the Acceptance Letter.

PSTC and D-RSC have been invited to submit a Qualification Plan (QP) for the DIMI biomarker panel, the second stage in the BQP process that details additional clinical studies and analysis for the intended Context of Use.

In concert with C-Path’s Duchenne Regulatory Science Consortium (D-RSC), on August 23, 2019 PSTC submitted a Qualification Plan (QP) to the U.S Food and Drug Administration (FDA) for glutamate dehydrogenase (GLDH) as a safety biomarker for detecting drug-induced liver injury (DILI) in clinical trials involving patients affected by inherited muscle disorders as well as muscle damage caused by strenuous exercise and drug-induced muscle injury. The submission received a positive response and has been accepted to FDA’s Center for Drug Evaluation and Research (CDER) Biomarker Qualification Program (BQP).

Click here to read the press release and view the Qualification Plan Determination.

PSTC and D-RSC have been invited to submit a Full Qualification Package, the final stage of qualification, that demonstrates clinical and analytical validity for the biomarker’s intended Context of Use.

The FDA has issued a Letter of Support to the Predictive Safety Testing Consortium (PSTC) to encourage the further study and use of a set of translational safety biomarkers to detect and monitor drug-induced pancreatic injury (DIPI). The set of biomarkers are four micro RNAs (miRNAs) under investigation for DIPI are miR-216a, miR-216b, miR-217, and miR-375.

The translational pancreatic safety biomarkers (miR-216a, miR-216b, miR-217, and miR-375) will be used in conjunction with amylase and lipase to aid in the detection of DIPI in Phase 1 clinical trials when there is demonstrated monitorability of induced damage in nonclinical studies and sufficient safety margins or when there is a priori concern that a drug candidate may induce DIPI due to known structural class similarities or identified target liability concerns.

Novel biomarkers of DIPI used in combination with currently available biomarkers could play an important role in guiding safety assessment in phase I clinical trials. Although the standard markers of pancreas injury, amylase and lipase, are currently the clinically accepted biomarkers for the diagnosis of acute pancreatitis (IAP/APA evidence-based guidelines for the management of acute pancreatitis, 2013), it is widely acknowledged that they are not sufficiently sensitive nor specific to guide dosing-related decisions in clinical trials (Lee and Papachristou, 2019; Ismail and Bhayana, 2017).

We support PSTC’s initiative to encourage the voluntary and complementary use of these miRNAs in conjunction with amylase and lipase as exploratory nonclinical and clinical biomarkers of DIPI. We also support PSTC’s generation of additional nonclinical toxicology data and plan for exploratory early clinical studies to enable future formal qualification of these safety biomarkers.

MiRNA molecules are short non-coding sequences ranging from 19 to 25 nucleotides in length, which are involved mainly in the post-transcriptional modulation of gene expression. A diverse array of functions including cellular signaling, cell growth and differentiation and apoptosis have been described for miRNAs. In humans, approximately 2,600 miRNA genes are currently known. Information on miRNA identification and nomenclature can be found at www.mirbase.org. Because of the relative abundance of miRNAs in specific tissues, they are increasingly being recognized as leakage biomarkers indicative of tissue injury (Bailey and Glaab, 2018; Schraml et al., 2017). A number of candidate miRNAs have been identified and studied in association with pancreatic acinar injury in nonclinical species (Erdos, 2020; Usborne, 2014), including miR-217, miR-216a, miR-216b, and miR-375.

Member companies of the PSTC PIWG have conducted studies and assessed pancreas-specific miRNAs to determine their performance in monitoring drug-induced toxicities. Toxicants targeting Exocrine/Acinar Predominant Injury (caerulein, caerulein perfusion, cholecystokinin, L-arginine, cyanohydroxybutene, DL-Ethionine, sodium taurocholate, Dibutyltin dichloride, Ethanol + Cyclosporin A + caerulein, ductal retrograde trinitrobenzene sulfonic acid, and proprietary drug candidates) and Endocrine/Islet Predominant Injury (streptozotocin and proprietary drug candidates) assessed the performance of the miRNAs to detect DIPI in rats (all toxicants) and dog (only cholecystokinin). The studies supporting this Letter of Support were published in peerreviewed scientific journals. These pancreas-specific miRNAs have been evaluated as biomarkers of DIPI and show promise to add value to the interpretation of amylase and lipase in monitoring acute pancreatic injury defined as acinar cell degeneration/necrosis.

More experience with the use of this biomarker in clinical studies would be useful to determine its utility more accurately for detecting and monitoring drug-induced pancreatic injury. MicroRNA thresholds have yet to be determined in clinical samples. Assessment will be in conjunction with amylase and lipase and not be used independently for decision making. Future studies will determine the clinical thresholds and the interpretation of results including performance metrics. We encourage exploration of these miRNAs (miR-217, miR-216a, miR-216b, and miR-375) used, in conjunction with amylase and lipase, to aid in the detection of DIPI in Phase 1 clinical trials when there is demonstrated monitorability of induced damage in nonclinical studies and sufficient safety margins or when there is a prior concern that a drug candidate may induce DIPI due to known structural class similarities or identified target liability concerns.

Any groups (academia, industry, government) that would like to join in this effort or have information or data that may be useful can contact Mr. Nicholas King (nking@c-path.org) or view the PSTC website.

The U.S. Food and Drug Administration (FDA) and European Medicines Agency, recently, issued Biomarker Letters of Support (LOS) for the skeletal muscle injury safety biomarkers myosin light chain 3 (Myl3) and skeletal muscle troponin I (sTnI), fatty acid binding protein 3 (Fabp3), and creatine kinase M (CK-M) based on data submitted by the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Skeletal Myopathy Working Group (SKMWG). These letters briefly describe the U.S. FDA’s and EMA’s thoughts on the value of Myl3, sTnI, Fabp3, and Ckm and encourage further evaluation of biomarkers with promising utility in drug development.

• FDA Letter of Support (January 22, 2015)
• EMA Letter of Support (March 6, 2015)

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA for the regulatory decision on use of serum/plasma Myl3, sTnI, Fabp3, and Ckm in nonclinical and exploratory clinical studies.

Decision tree for translational use of Myl3, sTnI, FABP3, and CK-M in a drug development program

Following the determination that Myl3, sTnI, Fabp3, and Ckm can add value to conventional biomarkers for monitoring skeletal muscle degeneration/necrosis in a prospective rat GLP study, sponsors are encouraged to discuss proposals for use of human Myl3, sTnI, Fabp3, and Ckm to enable the safe conduct of clinical studies with the appropriate regulatory review body.

The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), recently, issued Biomarker Letters of Support (LOS) for the drug-induced vascular injury safety biomarkers for the following: endothelial cell proteins (E‐Selectin, P‐Selectin, sICAM‐1, sICAM‐3, sVCAM‐1, thrombomodulin, and VEGF); smooth muscle cell proteins (EMA only: calponin, caldesmon); and inflammatory factors (CRP, GROa, NGAL, IL‐6, IL‐8, IP‐10, I‐TAC, MCP‐1, MIG, SAA, MIP‐1α, and TIMP-1) based on data submitted by the Innovative Medicine Initiative’s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Vascular Injury Working Group (VIWG).

• FDA Letter of Support (November 7, 2016)
• EMA Letter of Support (November 7, 2017)

These letters, describe the U.S. FDA’s and EMA’s thoughts on the value of the DIVI biomarkers and encourages further evaluation. The EMA’s LOS encourages “further nonclinical and exploratory clinical analyses to evaluate the translational relevance of changes in identified nonclinical DIVI biomarkers.” The FDA’s LOS encourages “additional use of these biomarkers to characterize their potential role for monitoring DIVI in early clinical drug development.”

Although not qualified by FDA or EMA, these translatable biomarkers, alone or in panel(s), are anticipated to reflect DIVI affecting vascular smooth muscle cells and endothelial cells, as well as the associated inflammatory response, as determined by histopathologic endpoints in rodents. It is envisioned that the vascular injury biomarkers will ultimately be used in healthy volunteers with no concurrent vascular disease to monitor for vascular safety in early clinical trials. These biomarkers will be used when such injury has been demonstrated to be monitorable by translatable biomarkers in animal studies of similar duration with the same test agent (including small and large molecule therapeutics). Applying the biomarkers in initial single and multiple ascending dose clinical studies could help inform planned dose escalations or continued dosing schedules.

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA for the regulatory decision on use of the DIVI biomarkers in nonclinical and exploratory clinical studies.

The U.S. Food and Drug Administration (FDA) and European Medicines Agency, recently, issued Biomarker Letters of Support (LOS) for the kidney safety biomarkers osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) based on data submitted by the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Nephrotoxicity Working Group (NWG).

The Summary Data Package reports the relationship between kidney proximal tubule degeneration/necrosis and urinary levels of OPN and NGAL in rodents. These letters briefly describe the U.S. FDA’s and EMA’s thoughts on the value of urinary OPN and NGAL and encourage further evaluation of biomarkers with promising utility in drug development.

• FDA Letter of Support (August 20, 2014)
• EMA Letter of Support (November 6, 2014)

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA for the regulatory decision on use of urinary OPN and NGAL in nonclinical and exploratory clinical studies.

Decision tree for translational use of urinary OPN and NGAL in a drug development program

Following the determination that OPN and NGAL can add value to conventional biomarkers for monitoring kidney tubular degeneration/necrosis in a prospective rat GLP study, sponsors are encouraged to discuss proposals for use of human urinary OPN and NGAL to enable the safe conduct of clinical studies with the appropriate regulatory review body.

The European Medicines Agency (EMA), recently, issued a Biomarker LOS,  for the drug-induced liver injury safety biomarkers Glutamate Dehydrogenase (GLDH) based on data submitted by the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Hepatotoxicity Working Group (HWG) and the Duchenne Regulatory Science Consortium (D-RSC).

• EMA Letter of Support (November 27, 2017)

This letter briefly describes EMA’s thoughts on the value of GLDH and encourages further evaluation. The EMA’s LOS supports “PSTC’s and D-RSC’s initiative to encourage investigation of the voluntary and complementary use of serum GLDH, in conjunction with currently used biomarkers of liver injury, as a clinical biomarker of liver injury. The Agency also supports PSTC’s generation of additional clinical safety data and plans for further clinical studies to potentially enable formal qualification of GLDH in the future.”

Decision tree for clinical use of GLDH

The U.S. Food and Drug Administration (FDA) issued Biomarker Letters of Support for the drug-induced liver injury safety biomarkers Cytokeratin 18 (CK-18), Total and hyperacetylated high mobility group protein B1 (HMGB1), Osteopontin, and Macrophage colony-stimulating factor 1 receptor (CSF1R) based on data submitted by the Innovative Medicine Initiative’s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Hepatotoxicity Working Group (HWG).

• FDA Letter of Support (July 25, 2016)

This letter briefly describes U.S. FDA’s thoughts on the value of CK-18, HMGB1, Osteopontin, and CSF1R and encourages further evaluation. The U.S. FDA’s LOS encourages further evaluation of biomarkers with promising utility in drug development either “alone or in combination as soluble monitoring biomarkers to assess the risk of progression of drug-induced liver injury (DILI) in patients in whom an initial DILI diagnosis has been established based on elevations of the standard biomarkers alanine aminotransferase (ALT) alone or in combination with total bilirubin (TBIL) as a clinical safety assessment in clinical trials in a drug development context.”

• Summary Data Package

The European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) have both issued separate Letters of Support (LOS) to encourage the further development and exploratory use of percent change from baseline of the following urinary markers: alpha-glutathione S-transferase (α-GST), clusterin (CLU), cystatin C (CysC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), albumin (ALB) and total protein (TPRO) as biomarkers of drug-induced renal tubular injury in early clinical trials. The EMA also supports the use of serum cystatin C utilizing the percent change from baseline approach proposed by the DIKI group. These Letters of Support are based on data submitted by the Innovative Medicine Initiative’s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T) and the Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium’s (PSTC) Nephrotoxicity Working Group (HWG).

• FDA Letter of Support (November 23, 2016)
• EMA Letter of Support (December 14, 2016)

These letters describe FDA’s and EMA’s thoughts on the value of α-GST, CLU, CysC, KIM-1, NGAL, OPN, ALB and TPRO and encourages further evaluation. The FDA’s LOS encourages “the exploratory use of these urinary biomarkers (α-GST, CLU, CysC, KIM-1, NGAL, OPN, ALB, and TPRO) as biomarkers of renal tubule injury in early clinical trials.”

Additionally, the FDA stated that the “exploratory human data suggests that the candidate drug-induced renal tubular injury biomarkers may be more sensitive and specific for the detection of acute kidney injury, especially when used in combination, than traditional means of monitoring for nephrotoxicity. In addition, you observed a rise in most of the candidate biomarkers (urinary a-GST, CLU, KIM-1, NGAL, CysC, and OPN) that preceded a clinically-relevant rise in sCr.”

The Summary Data Package contains summary statistics, description of analysis methods, and results tables submitted to the EMA and U.S. FDA.

• European Medicines Agency
• Pharmaceutical and Medical Devices Agency Japan
• U.S. Food and Drug Administration