How to ensure a definitive study

There is less margin for error with experienced staff in a quality clinical reasearch facility. Here are some key points to consider when selecting a clinic for thorough QT studies.

While numerous articles have been written concerning the regulatory status and analysis methods in a thorough QT study, little has been said about the actions required at the clinical research facility to assure a definitive study. According to Michael P Adams, Pharm D, senior vice president, clinical pharmacology services at SFBC International, the clinical research facility must take definitive steps to properly screen and recruit qualified subjects, control the study environment, minimise variation in electrocardiogram (ECG) collection, and manage potential safety issues associated with administration of supra-therapeutic doses of the investigational drug.

Many thorough QT study designs require the clinical research facility to recruit and successfully manage large cohorts (groups) of subjects, with parallel study designs often including 160 or more subjects balanced for age and gender. The number of cohorts should be minimised to avoid temporal differences in ECG measurements, and subjects must be carefully screened for the following:

• Abnormal cardiovascular history
• Electrolyte abnormalities
• Electrocardiogram abnormalities
• Potentially interfering concomitant medication use (including herbal products and dietary supplements)

Since screening electrocardiograms are very important, the investigator should have the expertise to verify the standard ‘machine read’ ECG and ensure the absence of abnormalities in conduction or repolarisation.

The clinical research facility must provide a controlled environment for the entire group of subjects across each successive cohort or study period, with sufficient highly trained staff members allocated throughout the data collection periods to ensure that all study procedures are executed correctly and on time. With cohort sizes of 40 subjects and frequent data collection intervals, this may require a large number of personnel dedicated to a single trial.

Technical awareness and data card protection

Given the wide array of instruments selected by various sponsors or core ECG laboratories, prior experience with multiple devices and their technical requirements is a definite plus. While modern devices are generally well shielded, testing should be considered when staff have no prior experience with the recording device. This will ensure proper training and, when conducted in the study room, verify the absence of unwanted electromagnetic interference. Consideration should be given to protection of data cards during the study period and transfer of the data to the core laboratory. Extra devices and cards should be available in the event of failure and study staff should confirm that devices are functioning properly prior to the first data collection time.

Lead placement and time management

The study staff must have the expertise to ensure correct lead placement throughout the collection interval. In addition to correct lead placement, minimising variability in data collection requires attention to subject positioning, activity level, timing of blood samples, vital signs and meals, and other factors (for example, use of peripheral electronic devices, including cell phones, MP3 players and laptop computers). Careful management of event timing, activities and the study environment must be replicated between baseline and treatment periods, between time points within a period and between cohorts. At the same time, the investigator and study staff must closely monitor subjects for evidence of toxicity, as there may be limited experience with the supra-therapeutic dose. Safety ECG recordings should be accurately read on site for signs of clinically significant changes.

Although most discussions of thorough QT studies focus on the myriad technical details, the critical impact that the clinical research facility, the investigator and the staff have on a successful outcome should not be overlooked. As with all aspects of clinical research, there is no substitute for expertise and careful attention to the most important details.