In the first use of a framework allowing submission of a single application to the two agencies, the FDA and the European Medicines Agency (EMEA) have 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, β2-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. 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.Beginning as the Division of Chemistry and then (after July 1901) the Bureau of Chemistry, the modern era of the FDA dates to 1906 with the passage of the Federal Food and Drugs Act, which added regulatory functions to the agency’s scientific mission.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Your toenails can tell you if you’re a candidate for heart disease sometime in the future. There’s a simple test that can predict your chances with almost 100% accuracy – and it all has to do with your 1) ___. Testing the level of 2) ___ in your toenail – whether or not you are a smoker – is a significant 3) ___ of possible coronary heart disease ahead. Non-smokers can also have high levels of nicotine in their bodies as a result of 4) ___ smoking. Toenail analysis has been tested on a group of 62,641 nurses who provided toenail clippings in 1982. Between 1984 and 1998, 905 of the nurses, developed coronary heart disease, and there was a direct 5) ___ to the levels of nicotine found in their toenails. Those who had the most nicotine also had a 3.4 times higher risk of heart disease, and each increase in the scale used to measure nicotine levels correlated to a 42% increased 6) ___. The analysis remained accurate even after the researchers adjusted for smokers and non-smokers. Analyzing the nicotine content of toenail clippings can also help gauge a woman’s heart disease risk. Toenail analysis could become a useful 7) ___ to identify high-risk individuals in the future, especially in circumstances when smoking history is not available or is subject to bias. Biomarkers of cigarette smoke exposure now used, such as the amount of 8) ___ (a nicotine breakdown product) in urine or saliva, only reflect exposure within the past few days. Because toenails grow 9) ___, they may offer a longer-term, more stable estimate of a person’s total level of 10) ___ to tobacco smoke. The women in the top fifth for toenail nicotine content were thinner, less active, heavier drinkers, and more likely to have high blood pressure or diabetes, as well as a 11) ___ history of heart attack, compared to those with less nicotine in their toenails. Also, the 905 women who had been diagnosed with heart disease had 12) ___ as much nicotine in their toenails, on average, as similar women without heart disease. After the researchers adjusted for other risk factors, they found that women in the top fifth for toenail nicotine had nearly four times the risk of heart disease compared to those in the bottom fifth. According to the authors, the findings suggest that measuring nicotine levels in the toenails “may improve the assessment of exposure and therefore our understanding of tobacco-related illnesses”. Source: American Journal of Epidemiology, 2008; 167: 1342-1348

ANSWERS: 1) toenails; 2) nicotine; 3) indicator; 4) passive; 5) match; 6) heart risk; 7) test; 8) cotinine; 9) slowly; 10) exposure; 11) family; 12) twice

Target Health Inc. has long been committed to being environmentally sensitive in our business practices. One approach is to provide a “paperless” environment for clinical research. We have already eliminated paper case report forms and paper queries with Target e*CRF®. Our latest PMA submission was done via eCOPY which eliminated one paper copy and an NDA submitted last year was fully paperless. Target Document® allows us to have a paperless Trial Master File and all faxes for projects are received directly into an eFax account and then uploaded directly into Target Document.

Please visit us at Booth 1261 at the Annual DIA Meeting in Boston. In addition to our full-service CRO capabilities, we will feature our paperless eClinical trial web-based toolbox including:

1. Target e*CRF® Version 1 with Batch Edit Checks
2. Target Document® – Paperless Trial Master File (TMF)
3. Target e*CTMS™ – Project Management Made Easy
4. Target Newsletter® – One Click Clinical Trial Information
5. Target e*CTR™ – eClinical Trial Record – Coming Soon

For more information about Target Health or any of our software tools for clinical research, please contact Dr. Jules T. Mitchel or Ms. Joyce Hays.