Setting the Standard
When technology rides ahead of our knowledge of how to handle it, standards become an issue. For this reason, governing bodies such as the FDA and the EMEA would do well to collaborate with both academic institutions and businesses to set the standards. The Critical Path Initiative (CPI) is the FDA’s national strategy for modernizing the sciences through which FDA-regulated products are developed, evaluated, manufactured, and used.
The CPI was launched in March 2004 to address the steep decline in the number of innovative medical products submitted for approval, despite the enormous breakthroughs being made in biomedical science. Although initially conceived as a drive to apply discoveries in emerging areas of science and technology to medical product development, the CPI has since expanded its scope to include all FDA-regulated products.
“Up until 2004, the FDA had some rather nonspecific guidelines, so the Critical Path was set up to address the safety and testing issues of potential and existing therapeutics and devices, as well as the tools that create them,” Craig Draper, Ph.D., senior product manager for multiplex assays at EMD Chemicals, a U.S. affiliate of Merck KGaA, explained at CHI’s recent “World Pharmaceutical Congress”.
One area of particular interest to EMD is drug-induced nephrotoxicity. “We have introduced new assays focusing on high-input kidney-toxicity assays and how they are being done,” concurred Scott Hayes, Ph.D., R&D director, assays. “Specifically, we have developed two 5-plex panels that detect markers for nephrotoxicity in preclinical studies using the rat model system.”
Dr. Hayes explained that drug-induced nephrotoxicity has been an ongoing concern, since studies often do not go on long enough to examine the effects of chronic, low-level kidney damage.
Several proteins were found to be specific biomarkers for kidney damage. Results were generated by Rules-Based Medicine using samples from Novartis and delivered to the CPI by the Predictive Safety Testing Consortium (PSTC). “These organizations and other members of the PSTC provided data that was used by the FDA and EMEA to develop guidelines on the use of the markers,” commented Dr. Draper.
Dr. Hayes also noted that “in the way many preclinical studies are set up with the current methodologies, it is easy to miss early-stage and low-level toxicity effects. There needs to be better sampling ability—and urine is an easy place to gather this information. The members of the PSTC screened many thousands of samples, enabling the FDA and EMEA to list the identified markers as being useful as markers of drug-induced nephrotoxicity, and data on these markers will assist with the regulatory decision-making process.
“EMD partnered with Rules-Based Medicine to develop multiplex kits that test several of the listed biomarkers, allowing companies to generate the data they need,” Dr. Draper said. “The end-user also has the option to outsource the testing, giving the customer a choice and flexibility on how they can generate the data they need.”
Dr. Hayes added that seven biomarkers have been confirmed. “Data from the two EMD panels using rat urine samples done with a collaborator in Germany showed significant fluctuations based on time points. For some test compounds, the longer the animal is exposed, the greater the toxicity over time.
“Compared to existing tests, this gives us a better idea of where the damage is and how it progresses. There is still data coming in about the damage that chronic use of drugs can do to the kidneys. Examining long-term levels of exposure is a crucial aspect of toxicity profiling. Existing tests are not sensitive to long-term, low-level chronic use, and that’s what we’re looking to change.”
As the technology gains traction, applications and opportunities abound. Personalized medicine is one area where the ability to run tests in parallel would be a boon. “The best way to service the elderly in the healthcare industry is to make it possible to test for everything in one place,” reported Steven A. Benner, Ph.D., Foundation for Applied Molecular Evolution (FfAME), at IBC’s “Tides Conference”. “As it is, patients travel from place to place to test for this and that. We need a way to make a genomic assay work—to understand from just one test what you need to know about the genetic part of a patient.”
Dr. Benner develops sets of reagents that allow detection of many DNA markers in low amounts in complex biological media. Mixing and matching these creates specific architectures that meet the specifications of the users.
“For example, look at infectious diseases; there are 100–1,000 markers that you would like to look for in a patient with a sore throat. Colon cancer is similar—for that you are still prescreening using a fecal blood test, which is not the best way to screen. If the colon cancer is bleeding, the disease has already progressed considerably,” notes Dr. Benner.
“In healthcare, we know the genetic markers for colon cancer, and we should be using those markers to give our patients much better care. You could test for diagnostic purposes and find the signal and part of the progression—if you can do this cheaply and multiplexed.”
Dr. Benner also adds that, while instrumentation and cell-based technologies have advanced dramatically in human diagnostics that target nucleic acids, novel reagents that deliver new capabilities to diagnostics architectures that target DNA and RNA are lagging behind. FfAME is working on advances in small molecule and protein reagents that permit highly multiplexed PCR, orthogonal capture, and highly selective priming, and their combinations in architectures that support oligonucleotide analysis, from detection of a few targets in circulating blood to personalized genome resequencing.
“When it comes to diagnostics, we have to do better for our patients,” said Dr. Benner.