Telemetric Monitoring Enhances Safety Pharmacology Research at IITRI

As drug development becomes more sophisticated, regulatory agencies require safety evaluation data sets that include specialized evaluations of organ function. To address the requirements of the International Conference on Harmonization (ICH) and the U.S. Food and Drug Administration (FDA), IITRI has enhanced its safety pharmacology services with the addition of telemetric monitoring of cardiovascular function. Having a staff with over 30 years of experience conducting safety pharmacology studies, IITRI continues to expand its capabilities with new talent and new technology in response to increased demand from sponsors in government and in the pharmaceutical and biotechnology industries.

Ya-Fei Chen, M.D., M.S., Research Toxicologist/Safety Pharmacologist, joined IITRI in 2005 to direct inhalation toxicology projects and to lead studies involving state-of-the-art safety pharmacology methods. A primary responsibility for Dr. Chen is to incorporate cardiovascular monitoring technology into IITRI's research and testing capabilities in safety pharmacology.

IITRI Responds to Regulatory Requirements

Prior to approving a drug for clinical trials, the FDA and other regulatory agencies require a core battery for safety pharmacology studies in which the effects of a test article on vital functions of the respiratory system, central nervous system (CNS), and cardiovascular system are evaluated. For many years, IITRI has performed studies to monitor pulmonary function (tidal volume, minute volume, respiratory rate, airway resistance, and dynamic lung compliance) in conscious rodent species. IITRI has also performed detailed evaluations of the effects of xenobiotics on the function of both the central and peripheral nervous systems, and is currently revalidating its CNS test methods. IITRI's test battery includes locomotor activity, motor coordination, two-way shuttle avoidance and acoustic startle response, and is commonly added to Functional Observational Battery evalutations performed in rodent and non-rodent species as part of safety assessment studies.

IITRI's approach to cardiovascular safety evaluation has been developed in response to ICH recommendations (ICH S7A: Safety Pharmacology Studies for Human Pharmaceuticals [2001], and ICH S7B: The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization [QT Interval Prolongation] by Human Pharmaceuticals [2005]). ICH guidelines indicate that data from unanesthetized and unrestrained animals is preferred for in vivo safety pharmacology testing, and state that "the avoidance of discomfort or pain is a foremost consideration" in the use of unanesthetized animals.

Telemetry Plays a Key Role in Cardiovascular Safety Assessment

The FDA specifically requires the submission of telemetric measurements for cardiovascular parameters with an Investigational New Drug (IND) application. In telemetry studies, a transmitting device implanted into test animals continuously transmits cardiac function data to a remote receiver using radio frequency communications, and allows evaluation of cardiac function in an anesthetized and unrestrained experimental animal. The cardiovascular parameters of interest for safety pharmacology are blood pressure, heart rate, and electrocardiogram (ECG) measurements. An ECG tracing depicts the electrical activity of the heart as it contracts - its depolarization (ventricular contraction) and repolarization (ventricular relaxation). The QT interval, the time between the QRS complex (depolarization) and the end of the T wave (repolarization), is a major focus of telemetry studies. According to Dr. Chen, "the major purpose of using telemetry technology is to assess the potential for a test compound to delay ventricular repolarization, hence to prolong the QT interval in the ECG waveform." Delayed ventricular repolarization may indicate an adverse impact of a test compound on cardiac function.

A significant advantage of telemetry is that animals are tested under conditions closer to their natural state than when using conventional methods. Unrestrained motility and the lack of anesthesia effects are closer to the real-life situations in which a human would be treated with a new drug. Additionally, the ability to collect a complete set of continuous data for long periods of time, directly from the test system, increases the accuracy of the study. This type of data collection may reveal facts about test compounds that interrupted data might not. Clearly, the advantages of telemetric research have enhanced the reliability of safety assessment research.

Validation and Conduct of Telemetry Technology at IITRI

A canine model has been widely used in QT prolongation studies. IITRI has purchased a telemetry system for monitoring cardiovascular parameters in canine species, and completed a series of validation studies prior to implementation of the technology in Good Laboratory Practice (GLP)-compliant studies. The telemetry system was initially validated using a signal simulator for monitoring cardiovascular parameters, followed by validation studies using conscious, free-moving animals.

	A canine model has been widely used in QT prolongation studies. IITRI has purchased a telemetry system for monitoring cardiovascular parameters in canine species.

At IITRI, animals are generally monitored for selected periods over several weeks to monitor body temperature, blood pressure, heart rate and ECGs, as well as routine toxicologic endpoints such as clinical observations, body weight, and food consumption. For the safety of the animals and the integrity of the study, the IITRI staff veterinarian ensures the animals are completely recovered from device implantation surgery and that their vital signs are comparable to pretest reference data before a study is initiated.

In addition to the QT interval, standard cardiovascular assessments at IITRI include the RR (interval between two consecutive R waves on the ECG), PR (interval between the P and R waves on the ECG), QRS complex and QTc (the correction of the QT interval based on the heart rate using a correction formula) intervals on the ECG, as well as blood pressure (systolic, diastolic and mean arterial) and heart rate measurements.

Telemetry Studies Support Pharmaceutical Development

Access to telemetry technology is necessary for pharmaceutical and biotechnology companies to provide comprehensive safety assessments of new pharmaceuticals and biologicals. While telemetry had been used in research for approximately 10 years prior to the 2001 ICH recommendation, it has emerged as a central requirement to obtain FDA approval for administration of a novel drug to humans. Without uninterrupted demonstration of the effect of a test substance on cardiovascular parameters, the regulatory agency will not approve an IND. IITRI's ability to provide these services allows it to assist pharmaceutical and biotechnology companies that lack the facilities, instrumentation, or expertise to conduct safety pharmacology studies in-house.