38 June 20 08 VIEW on Clinical Operations QT TRIALS T he ICH E14 gives guidance regarding the conduct of socalled “Thorough QT Trials (TQT).” While discussions around this guidance occurred well before the final adoption of the doc ument, little was said about classes of drugs where a classic TQT study was not possible — oncology compounds and biologics to name two. Compounds that presented a risk in healthy patients were not thought to be a priority. Relatively recently, regulato ry agencies have shown an increased interest in these compounds and have required a QT investigation. These “notsothorough” trials have taken the informal name of “Intensive QTTrials.” Inclusion Criteria An Intensive QT trial includes many aspects found in a TQT trial, including triplicate ECGs and multiple collection time points, but they vary from aTQT design in some very fundamental ways.These differences can include type and number of subjects, lack of a placebo arm and the use of a positive control. Intensive QT studies tend to use the patient population instead of the healthy volunteers normally found in the TQT trial. Use of a patient population increases the number of possible concomitant dis eases, thus possibly increasing the variability of the QT measurement. The design of the intensive study is generally an open label study. It can be part of a dose escalation study where ECGs are collected dur ing each dose. Since the primary endpoint of these studies is not QT interval measurements, many of these studies are not powered ade quately to consider them a TQT study. Due to the nature of the illnesses that these compounds treat, the statistical analysis is not as focused on the 10 ms upperbound for the 95% CI for QT prolongation. Outliers, especially those with new QTc prolongations greater than 500 ms, however should be categorized. A placebo arm is, in most cases, not used in these trials. In a large proportion of these studies, a placebo arm is considered unethical. Comparisons with a predose baseline must serve for the statistical comparison. Baseline measurements can be taken approximately one hour before dosing. Many companies resist using a positive control. In some instances, a positive control can still be used in a leadin fashion. Since moxifloxacin has a relatively short halflife, it has been used in some studies. If a pos itive control is not considered appropriate, justification must be made to the agency. Although these trials are mainly focused on the QTinterval, con sideration should be given to overall cardiac safety. Compounds used in intensive QT trials can be highly toxic and thought should be given to supplementing the ECG analysis with echocardiography and imaging. These modalities should be part of an overall cardiac assessment. A Work in Progress While discussion continues around this area, and although guidelines are being developed, at this writing, there are no currently agreed upon guidelines for QT assessment in oncology agents, biologics, or large molecules.The agency is requiring data for these compounds with an eye on whether or not these trials will be needed in the future. It is recom mended that the sponsor include as many elements for theTQT paradigm as possible in the intensive QT trial.The data should be as robust as pos sible without hindering patient safety and ethical considerations. Consulta tion with the agency is also recommended. The QT interdisciplinary review team will have the latest scientific and regulatory thought process for compounds that will not be appropriate for a TQT trial. # Biomedical Systems BIOMEDICAL SYSTEMS, St. Louis, is a global provider of centralized diagnostic services for clinical trials. For more information, visit biomedsys.com. Intensive QT Trials — “The NotSoThorough QT Study” It is recommended that the sponsor include as many elements for theTQT paradigm as possible in the intensive QT trial. The data should be as robust as possible without hindering patient safety and ethical considerations. Timothy Callahan, Ph.D. Chief Scientific Officer 0608 pvv layout FINAL 5/29/08 11:44 PM Page 38

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