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FDA, European Medicines Agency to Consider Additional Test Results When Assessing New Drug Safety -Collaborative effort by FDA and EMEA expected to yield additional safety data
  June 12, 2008
In the first use of a framework allowing submission of a single application to the two agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) worked together to allow drug companies to submit the results of seven new tests that evaluate kidney damage during animal studies of new drugs. The tests measure the levels of seven key proteins or "biomarkers" found in urine that can provide additional information about drug-induced damage to kidney cells, also known as renal toxicity.
The new biomarkers are KIM-1, Albumin, Total Protein, β:2-microglobulin, Cystatin C, Clusterin, and Trefoil Factor-3. For decades, both FDA and EMEA have required drug companies to submit the results of two blood tests, called blood urea nitrogen (BUN) and serum creatinine, to evaluate renal toxicity. In addition to those tests, the FDA and EMEA will now consider results from the seven new tests as part of their respective drug review processes. Although a decision by the sponsor to collect information using the new tests is voluntary, if collected, it must be submitted to FDA.
"The development of these and other biomarkers can result in important tools for better understanding the safety profile of new drugs," said Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research. "We hope these biomarkers will lead to human tests that detect drug-induced kidney injury in people earlier than is now possible, and help health care professionals better manage potential kidney damage from drugs."
Woodcock added that such human tests could one day open the door to the approval of more powerful drugs, especially for diseases where renal toxicity currently prevents promising experimental drugs from being approved. With more sensitive tests for renal toxicity, FDA could approve such drugs because health care professionals could closely monitor patients and halt the drug if early signs of renal toxicity appear.
Development of the new biomarkers was led by the Predictive Safety Testing Consortium (PSTC), whose members include scientists from 16 pharmaceutical companies. The PSTC was organized and led by the Critical Path Institute, a nonprofit organization that works to support FDA research collaborations that improve the development of medical products.
Researchers from Merck & Co., Whitehouse Station, N.J., and Novartis AG, Basel, Switzerland, identified the new biomarkers, tested them to prove their accuracy and usefulness, and then shared their findings with the other consortium members for further study. The consortium then submitted applications for use of the biomarkers to FDA and EMEA.
The project is the first in which a group of drug companies has worked together to propose and qualify new safety tests and then present them jointly to the FDA and EMEA for consideration. The FDA and EMEA laid the groundwork for these specific joint-agency biomarker reviews in 2004 when they developed a framework called the Voluntary Exploratory Data Submission review process.
The new process allowed the PSTC to submit a single biomarker data application to both regulatory agencies, and then to meet jointly with scientists from both agencies to discuss it in detail and to address additional scientific questions posed by the regulators. Each regulatory agency then reviewed the application separately and made independent decisions on use of the new biomarkers.
FDA scientists believe that the seven new tests may provide important advantages over the BUN and creatinine tests. For example, in experiments using rats, the two traditional tests can only detect kidney damage a week after it has begun to occur. The new tests, however, are more sensitive and can detect cellular damage within hours. And while BUN and serum creatinine show that damage has occurred somewhere in the kidneys, the new tests can pinpoint which parts of the kidney have been affected.
The seven new tests were developed and will be carried out initially in rats. These tests were selected because other studies have shown that identical biomarkers are produced in human kidney cells. While the FDA and EMEA will consider these biomarkers in rat studies initially, the PSTC has begun work to further qualify the biomarkers for use in human studies. If successful, the PSTC will present a new biomarker data application to the two agencies to seek acceptance of the human biomarkers.
The Predictive Safety Testing Consortium (PSTC) is a unique public-private partnership, led by the non-profit Critical Path Institute (C-Path), that brings together pharmaceutical companies to share and validate each other's safety testing methods under advisement of the Food and Drug Administration ("FDA") and its European counterpart, the European Medicines Evaluation Agency ("EMEA"). The 17 corporate members of the consortium share internally developed pre-clinical safety biomarkers in five workgroups: carcinogenicity, kidney, liver, muscle and vascular injury.
The PSTC was officially announced on March 16, 2006 by Health and Human Services Secretary Michael Leavitt, FDA Commissioner Dr. Andrew von Eschenbach and FDA Deputy Commissioner Dr. Janet Woodcock who identified the consortium as "unprecedented" and a "shining example" of the type of work the FDA would like to see conducted.
The tests that are used to determine drug safety today have not changed in decades. Companies have developed newer safety testing methods, but these are not generally accepted by the FDA or EMEA as proof of safety because the tests have not been independently validated by a third party. Also, the methods used by companies are often different, leaving regulatory scientists unclear about which methods should be preferred.
In order to find improved testing methods, C-Path has invited pharmaceutical companies to join the PSTC in which they share their internally developed methods and then test the methods developed by another member of the Consortium. Ten EMEA and nineteen FDA scientists participate as advisors, along with more than 190 participating scientists, with C-Path serving as the "trusted third party," leading the collaborative process, collecting and summarizing the data.
Consortium members are sharing their new pre-clinical biomarker tests for examination and cross-validation by other members of the Consortium. The process is expected to enable the FDA and EMEA to write new Guidances for industry that identify more accurate methods to predict drug safety. Notably, the FDA and EMEA scientists are not acting in their usual role as regulators. Instead they are active participants, providing assistance and advice to the Consortium.
Early Results.
This unprecedented sharing of data by the industry facilitated the FDA's and EMEA's piloting of data submission processes to receive, review and approve new methods as qualified for use in drug development. In May 2008, the FDA and EMEA confirmed their joint review and acceptance of seven new laboratory tests on urine which signal kidney injury. The protein signals, known as biomarkers, were confirmed in data from rat studies submitted to the FDA and EMEA by the PSTC. The FDA and EMEA jointly came to the conclusion that:
· the kidney biomarkers are acceptable in the context of non-clinical drug development for the detection of acute drug-induced kidney toxicity;
· the kidney biomarkers provide additional and complementary information to the currently available standards;
· the use of kidney biomarkers in clinical trials is to be considered on a case-by-case basis in order to gather further data to qualify their usefulness in monitoring drug-induced kidney toxicity in man.
The newly accepted biomarkers are KIM-1, Albumin, Total Protein, b2-Microglobulin, Cystatin C, Clusterin and Trefoil factor-3. The use of these new tests can now be used in laboratory research to predict the safety of experimental drugs, allowing drugs to reach market faster and with greater confidence in their safety. The PSTC is actively involved in research to further qualify the biomarkers for use in clinical drug development.
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