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Cardiac Safety Concerns For Prolonged QT
Over the past several years cardiac safety concerns have been the primary reason for the FDA to call for the withdrawal of a drug from the market, limit a drug’s indications, or deny pharmaceutical companies the approval to market a drug. One of the major issues of concern is a drug induced delay in cardiac repolarization. For that reason, the FDA and other international regulatory organizations have requested pharmaceutical companies and biopharmaceutical companies to conduct more intensive testing for cardiac safety related issues with protocol designs now known as Thorough QT studies.
What Are Thorough QT Studies?
FDA guidelines indicate the need for additional cardiac safety testing when a positive signal for QT prolongation is found in pre-clinical development of a compound. Thorough QT Studies use precise methodologies to detect and evaluate the QT
interval prolongation of small magnitudes to better assure a new drug’s cardiac safety.
Per the ICH E14 Document, a protocol for a Thorough QT Study recommends:
- Conducting the trial early in a drug’s development, though not as a first-in man-study
- Recruiting healthy volunteers
- Acquiring ECGs that have:
- Triplicate measurements
- Time matched timepoints
- Timepoints around the Cmax
- Using a Positive Control to establish assay sensitivity
For more information on Biomedical Systems TQT Services, please click here.
TQT Newsletter
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The FDA Warehouse and aECG 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 was 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 over 650,000 ECGs now in the warehouse transmitted by a number of different Sponsors and ECG core labs.
Once the data is 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 re-read 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 is unacceptable, the reviewer can require the ECGs to be re-measured.
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