How an Unlikely Alliance is Revolutionizing Drug Safety
Imagine taking a medication that effectively treats your condition but causes undetected damage to your kidneys—damage that traditional tests might only discover when it's too late. For decades, this scenario has been a silent challenge in medicine. Current drug safety tests haven't significantly evolved in half a century, relying on indicators that often detect injury only after substantial damage has occurred 1 .
Enter the Predictive Safety Testing Consortium (PSTC), a groundbreaking collaborative effort that brings together competing pharmaceutical companies, regulatory agencies, and academic institutions to develop better ways to monitor drug safety 1 2 3 .
Founded in 2006 under the Critical Path Institute, this "pre-competitive" consortium operates on a simple but revolutionary principle: when it comes to fundamental drug safety, everyone benefits from working together 1 3 . By sharing data and expertise across organizational boundaries, the PSTC has achieved what no single company could accomplish alone—developing and gaining regulatory acceptance for novel safety biomarkers that can detect drug-induced injuries earlier and with greater precision than ever before 1 .
Traditional drug safety assessment relies heavily on decades-old biomarkers that have significant limitations. Serum creatinine and blood urea nitrogen (BUN), the standard indicators for kidney damage, are known as "lagging indicators" because they only show abnormal levels after substantial injury has already occurred 7 . Similarly, for liver injury assessment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) lack specificity—they can become elevated due to muscle injury or other conditions unrelated to liver damage, creating confusion about the true source of toxicity 6 .
When each pharmaceutical company uses different proprietary methods to test drug safety, regulatory scientists at agencies like the FDA face significant challenges in interpreting results and determining which methods should be trusted 1 .
Without independent validation and standardization, promising new safety tests remain exploratory tools rather than accepted standards for decision-making. This inconsistency ultimately slows down drug development and potentially compromises patient safety.
| Organ | Traditional Biomarkers | Key Limitations |
|---|---|---|
| Kidney | Serum creatinine, BUN | Lagging indicators; only elevate after significant damage 7 |
| Liver | ALT, AST | Not specific to liver; can elevate with muscle injury 6 |
| Pancreas | Amylase, lipase | Not sufficiently sensitive or specific 1 |
| Muscle | Various muscle enzymes | Lack specificity for muscle injury types 1 |
The formation of the PSTC marked a dramatic departure from traditional competitive practices in the pharmaceutical industry. Officially announced by FDA Commissioner Dr. Andrew von Eschenbach and FDA Deputy Commissioner Dr. Janet Woodcock in 2006, the consortium was described as "unprecedented" and a "shining example" of the type of work the FDA wanted to see conducted 1 .
The consortium tackles the challenge that biomarker qualification requires data from many compounds and studies, making it prohibitive for any single organization 2 .
The PSTC's work on kidney safety biomarkers represents one of its most significant successes and illustrates the consortium's systematic approach to biomarker qualification. The Nephrotoxicity Working Group began by identifying a panel of promising novel urinary biomarkers that showed potential for detecting kidney injury earlier and with greater specificity than traditional markers 7 .
The consortium conducted more than 90 nonclinical studies across multiple institutions, treating rats with known nephrotoxicants and comparing the performance of novel biomarkers against traditional ones and, most importantly, against direct histopathological evidence of kidney damage 1 7 .
Before any clinical studies could be meaningful, the consortium had to develop and validate standardized laboratory methods to ensure consistent measurement of these biomarkers across different facilities and platforms 1 .
The team then analyzed data from clinical studies, including a Normal Healthy Volunteer Study and a collaborative Harvard-Merck study of cancer patients treated with cisplatin (a chemotherapy drug known to cause kidney injury) .
After years of data generation and analysis, the PSTC submitted a comprehensive package to regulatory agencies, ultimately leading to the first-ever qualification of clinical safety biomarkers by the FDA in 2018 .
| Biomarker | Abbreviation | What It Detects | Advantage Over Traditional Markers |
|---|---|---|---|
| Kidney Injury Molecule-1 | KIM-1 | Specific to proximal tubule injury 7 | More specific and earlier detection |
| Neutrophil Gelatinase-Associated Lipocalin | NGAL | Early response to kidney injury 1 | Rapid response, appears sooner than creatinine |
| Clusterin | CLU | Tissue damage and repair response 1 | Indicates ongoing injury processes |
| Cystatin C | CysC | Glomerular filtration rate changes 1 | More sensitive than creatinine for filtration changes |
| Osteopontin | OPN | Inflammatory response in kidney 1 | Indicates specific injury mechanisms |
| Trefoil Factor-3 | TFF-3 | Tubular damage marker 7 | Specific to certain injury types |
The process of transforming a promising laboratory observation into a regulatory-accepted tool is formalized through the Biomarker Qualification Process 7 . This multi-stage pathway begins with a Letter of Intent submitted to regulatory agencies, outlining the proposed biomarker and its intended "Context of Use" 1 7 .
| Year | Regulatory Milestone | Significance |
|---|---|---|
| 2008 | Qualification of 7 rodent kidney safety biomarkers 1 | First biomarkers qualified through PSTC collaboration; accepted by FDA, EMA, PMDA |
| 2014 | Letters of Support for kidney and muscle injury biomarkers 1 | Regulatory encouragement for further development of promising biomarkers |
| 2018 | First qualification of clinical safety biomarkers (kidney) | Historic first; allowed use in Phase 1 clinical trials |
| 2019 | Qualification Plan accepted for muscle injury biomarkers 1 | Progress toward qualification for new organ systems |
| 2025* | Planned submission for new kidney biomarker panel 5 | Ongoing work to expand biomarker utility |
*Planned future submission
This process represents a significant evolution in regulatory science, creating a transparent pathway for validating new drug development tools. The 21st Century Cures Act formally recognized this process, cementing the qualification of drug development tools in U.S. law 7 .
While the kidney safety biomarkers represent a major achievement, the PSTC has extended its collaborative approach to other critical organ systems. Each working group faces unique scientific challenges while following similar principles of data sharing and consortium-based validation.
This group has advanced glutamate dehydrogenase (GLDH) as a more liver-specific alternative to traditional liver enzymes 6 . Unlike ALT and AST, GLDH is primarily found in liver mitochondria, making it less likely to elevate due to muscle injury. The consortium recently submitted a Full Qualification Package for GLDH to the FDA, marking a significant milestone toward regulatory acceptance 6 .
This group addresses the challenging problem of detecting drug-induced damage to blood vessels, a known liability of certain drug classes. This group is exploring novel biomarkers that can distinguish between different types of vascular injury and determine their relevance to human risk 3 .
The consortium, in collaboration with the Duchenne Regulatory Science Consortium, has submitted a Letter of Intent for a panel of four novel biomarkers that may offer better specificity for detecting drug-induced muscle damage compared to traditional enzymes 1 .
Most recently, the consortium has explored innovative approaches like microRNAs for detecting drug-induced pancreatic injury—a condition particularly difficult to monitor with traditional tests 1 . The FDA has issued a Letter of Support encouraging further development of these biomarkers, acknowledging their potential to address a significant unmet need in drug safety assessment 1 .
The Predictive Safety Testing Consortium represents more than just a series of scientific advances—it embodies a fundamental shift in how drug safety science is conducted. By creating a pre-competitive space for sharing data and expertise, the PSTC has demonstrated that collaboration can achieve what competition cannot: broadly accepted, independently validated tools that benefit the entire pharmaceutical ecosystem 1 3 .
Improved safety biomarkers enable drug developers to detect potential injuries earlier in the development process 1 .
These advances translate to enhanced patient safety in clinical trials and, ultimately, for people taking medications worldwide.
Promising medicines can move forward with greater confidence, accelerating the drug development process.
The story of the PSTC reminds us that some of the most significant advances in medicine come not from individual discoveries but from new ways of working together, transforming silent risks into detectable signals, and building a safer future for drug development—one biomarker at a time.