On Aug. 11, 2006, 16 representatives from ECG core labs located around the world convened in Milwaukee, Wisc., for a one-day meeting with Dr. Norman Stockbridge, Head of the Cardio-Renal Board of the Food and Drug Administration. Topics covered ranged from recent developments instituted by the FDA in relation to conducting a Thorough or Definitive QT study (TQT) to requirements for submissions to the FDA ECG Warehouse. While the agenda was broad, it gave members of the ECG core lab community and the FDA a chance to have an open discussion in a neutral setting concerning matters that greatly affect safety and efficacy of compounds from the cardiac perspective. QT Interdisciplinary Working Team (QTIRT) Dr. Stockbridge informed the group that the FDA had established a team dedicated to the review of all TQT protocols and was tasked with making recommendations regarding data collection and analysis. The team is comprised of a pharmacologist, a clinical pharmacologist, a medical officer, a statistician, and a data manager. While the data collected will be reviewed by QTIRT, the decisions from this group are non-binding and therefore can be overturned by the division that is reviewing the drug. The FDA Warehouse and ECG Submissions Based on recommendations from the 2003 QT Concept Paper, the precursor of the ICH E14, The Clinical Evaluation of QT/QTc Interval Prolongation Potential For Non-Antiarrhythmic Drugs, it was determined that it would be critical to have annotated ECG waveform data for studies that definitively address the effects of a drug on ventricular repolarization. To ensure that the data were consistent between sponsors and trials, a standardized reporting format was needed. This requirement led to the HL7 and the XML format, which is now the language for all ECGs transmitted to the warehouse. The FDA entered into a Cooperative Research and Development Agreement (CRADA) with Mortara Instruments to design a repository to house and manage the massive number of ECGs that would be required for these trials. As of February 2007, it is reported that there are more than 650,000 ECGs now in the warehouse transmitted by a number of different sponsors and ECG core labs. Once the data are received into the warehouse, the FDA reviewer has the ability to review the ECGs, for quality and inconsistencies using a tool-set developed specifically for this purpose. The reviewer will not systematically reread the ECGs apart from looking at those ECGs that are flagged by the data quality tools provided in the tool set. If, in the reviewer’s estimation, the data are unacceptable, the reviewer can require the ECGs to be remeasured. Biologics and Oncolytics in the TQT Paradigm Two additional topics were addressed with Dr. Stockbridge this past August; biologics and oncology compounds as they relate to TQT studies. Biologics have recently become of interest in the TQT paradigm. Some large molecules have shown a propensity to prolong the QT interval. Therefore, the FDA is starting to investigate the possibility of including biologics into the TQT requirements. Oncolytics, on the other hand, present another set of issues for sponsors in clinical trials. Since these compounds cannot be given to healthy subjects, it is impossible to apply the guidelines as written in the ICH E14. Yet it is still imperative to understand the cardiac safety profile that these drugs have on the QT interval. The oncology group within the FDA is working through the process on how to handle these problems. If a TQT is deemed necessary, one option will be to make the therapeutic dose the highest dose. But it is more likely that the sponsor will be able to do routine cardiac safety investigations of oncolytics. Where Do We Go From Here? Meetings of this type are important not only to the core labs but to the pharmaceutical industry as a whole. They help maintain open lines of communication between all parties involved in drug development and focus attention on areas that need to be addressed. One of the issues that the FDA and Dr. Stockbridge would like to see improved is the tool set currently being used by the FDA Warehouse. Hopefully all ECG core labs will be able to contribute to this project to improve the overall quality and reporting functions for the FDA and the warehouse. Regulatory Issues Kevin J. Klingler, President, Pharmaceutical Services April 2007 VIEW on Biotechnology Biomedical Systems, St. Louis, is a global leader in core diagnostic services for the pharmaceutical industry. For more information, visit biomedsys.com. Cardiac Safety and Efficacy An Open Discussion
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