WO2006065765A2

WO2006065765A2 - System for monitoring physiological parameters for pharmaceutical development

Info

Publication number: WO2006065765A2
Application number: PCT/US2005/044967
Authority: WO
Inventors: Regina E. Dugan
Original assignee: Quantum Applied Science & Research, Inc.
Priority date: 2004-12-14
Filing date: 2005-12-14
Publication date: 2006-06-22
Also published as: WO2006065765A3

Abstract

A physiological sensing system ((10) for monitoring a test subject (55) during drug development comprises a support article (20) including a capacitive-type sensor (60-62) for sensing and providing data on a first physiological parameter of the test subject (55). An analysis unit (40) is adapted to communicate with the support article (20) to receive data on the first physiological parameter and to analyze the first physiological parameter data based on a normative data set, with the analysis unit (40) being adapted to generate a pharmacovigilance report based on the analyzed first physiological parameter data.

Description

SYSTEM FOR MONITORING PHYSIOLOGICAL PARAMETERS FOR PHARMACEUTICAL DEVELOPMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims the benefit of U.S. Provisional Patent Application Serial No. 60/635,597, filed December 14, 2004 and U.S. Provisional Patent Application Serial No. 60/635,480, filed December 14, 2004.

STATEMENTREGARDINGFEDERALLYSPONERED RESEARCHORDEVELOPEMENT

The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of Phase II SPIR Contract No. W31P4Q-04-C-R293 awarded by DARPA. BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally pertains to the art of measuring and analyzing physiological signals to determine the effects of pharmaceuticals on a test subject.

2. Discussion of the Prior Art

It is known in the art that multi-sensor systems can be used to assess the state of a human or animal. Such systems typically incorporate off-the-shelf sensors into an integrated system and are utilized to assess the qualitative state of an athlete or to improve a subject's ability to achieve general health goals such as weight loss. See, for example, U.S. Patent No. 6,551 ,252. Common sensors in use include, but are not limited to, temperature sensors, accelerometers, galvanic skin response, heart rate detectors, and electrocardiogram (ECG) electrodes.

The monitoring of induced adverse effects, particularly cardiac abnormalities, is an important element in establishing the safety of a particular pharmaceutical. Monitoring of the quality, safety and efficacy of a marketed medicine is known as Pharmacovigilance. This is an ongoing process that takes place both during the development of drugs and continues once the drugs have been released onto the market. It is well known in the industry that cardiotoxicity, or other adverse effects on the heart, can result in the safety- withdrawal of otherwise successful pharmaceuticals. For example, five of the twelve safety-based withdrawals of drugs from the market between 1997 and 2001 were the result of heart rhythm and/or valve risks. The recent high-profile withdrawal from the market of the drug Vioxx® by Merck &Co. was reportedly due to an increased risk of serious cardiovascular events.

Drug-induced changes in cardiac repolarization may lead to the induction of potentially lethal arrhythmias, and the phenomenon has recently attracted substantial research and regulatory attention. The pharmaceutical industry and its regulatory bodies have accepted that studying the effects of a drug on the so-called QT interval of the heartbeat as shown in a surface ECG is the best method for predicting possible cardiotoxic effects of a drug. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, and is an indirect measurement of the time between ventricular depolarization and repolarization. Prologation of the QT interval can be a precursor to the unstable ventricular tachycardia Torsade des Pointes (TdP). The International Conference on Harmonization's formal document covering how the cardiac safety of a new drug should be determined was released in May of 2005. This conference was tri- partate, with participation from Japan, the European Union and the United States, and its guidelines are to be adopted by the regulatory bodies of all three countries. These guidelines state that, early in clinical development, drugs should be subjected to a trial in which otherwise healthy subjects taking the drug undergo ECG monitoring and the drug's effect on the QT interval of these subjects should be assessed. This is known as a "thorough QT study."

Present studies that look for drug-induced changes in the QT interval of the patient population are limited by the complexity and expense of procedures to obtain consistent, long-term 12-lead ECG measurements. After an initial drug-free calibration period, the studies typically restrict patient monitoring to several hospital visits, collecting 10 seconds of ECG data at a time. Such studies are prone to error because of the variety of factors that naturally influence the QT interval such as circadian rhythm, food intake, activity level, and heart rate hysteresis. While clinical drug studies seek to measure the QT interval of a patient population with 5 millisecond (ms) precision (as dictated by Federal Drug Administration (FDA) guidelines), the QT interval even when corrected by accepted factors has been shown to vary by over 30 ms during the course of an hour in a healthy subject.

In order to get a comprehensive assessment of a drug's effect on cardiac function, an ideal study would monitor the subjects' QT interval throughout the day over extended period of time. However, present 12- lead ECG recording systems, such as the standard hospital system or Holter monitor, are poorly suited to such long-term monitoring. The patients have to transport themselves to the hospital each time an ECG is to be recorded, since clinicians are needed to prepare the skin and properly position all the electrodes. This entails considerable effort by the patient and expense for healthcare professionals. Alternatively, leaving the wet electrodes in place for long periods is undesirable because they are intrusive and uncomfortable.

Prior methods of measuring electric potentials associated with human or animal subjects employ the use of gels or sticky pads in order to establish electrical contact between the skin and the electrode, or the insertion of electrodes into the body. More specifically, electrodes that make a resistive (i.e. Ohmic) electrical contact have been predominantly employed in connection with measuring electric potentials produced by animals and human beings. The disadvantages of such resistive electrodes have been described previously and include discomfort for the patient, the requirement for conducting gels and/or adhesives, difficulty in establishing good electrical contact because of differing physical attributes of the subject (hair, skin properties, etc), and the degradation in resistive coupling quality over time, among others. Repeated attachment or prolonged use of such electrodes have been shown to cause excessive skin irritation, and would not be accepted by most in a significant population study. These limitations have created a significant barrier to the use of resistive electrodes over extended periods of time and/or when convenience of use is paramount.

Another type of sensor that has been proposed in measuring biopotentials is a capacitive sensor. Early capacitive sensors required a high mutual capacitance to the body, thereby requiring the sensor to touch the skin of a patient, or test subject. The electrodes associated with these types of sensors are strongly affected by lift-off from the skin, particularly since the capacitive sensors were not used with conducting gels. As a result, capacitive sensors were not been found to provide any meaningful benefits and were not generally adopted over resistive sensors. However, advances in electronic amplifiers and new circuit techniques have made possible a new class of capacitive sensor that can measure electrical potentials when coupling to a source on the order of 1 pico Farad (pF) or less. This capability makes possible the measurement of bioelectric signals with electrodes that do not need a high capacitance to the subject, thereby enabling the electrodes to be used without being in intimate electrical and/or physical contact with the subject. Such capacitive-type sensors and sensing systems have been previously disclosed. See, for example, U.S. Patent Application Publication No. 2005/0054941 disclosing a physiological monitoring garment having sensors utilizing capacitive coupling.

SUMMARY OF THE INVENTION

The present invention is directed to a physiological sensing system for monitoring a test subject during drug development. The system comprises a support article including a capacitive-type sensor for sensing and providing data on a first physiological parameter of the test subject, an electronics unit in communication with the sensor, and a power unit in communication with the electronics unit and the sensor. The support article is adapted to hold the sensor in proper physical orientation on the test subject for collecting the data on the first physiological parameter. An analysis unit includes a data processor and a communications device. The analysis unit is adapted to communicate with the support article to receive data on the first physiological parameter and to analyze the first physiological parameter data based on a normative data set. The analysis unit further is adapted to generate a report based on the analyzed first physiological parameter data. Further, a base station including a user interface, a data processor and a communications device, the base station is adapted to communicate with the support article to receive data on the first physiological parameter.

The raw data obtained with the system are processed by known algorithms for obtaining QT/QTc and heart rate variability (HRV) information. The advantage of the present invention is that it offers the possibility of easy and comfortable long-term monitoring, thus allowing for the removal from the data of variations of the heart's electrical function caused by circadian rhythms, activity, food intake, heart rate hysterisis and other outside factors. This long-term collection and analysis of data results in QT/QTc values more reflective of drug-induced changes than those obtained by current monitoring practices.

A further use of the present invention is as part of an integrated pharmacovigilance system comprised of a sensor system for unobtrusively measuring physiological signals from a test subject, and an integrated data analysis and interpretation system for collecting, interpreting, and analyzing safety signals throughout the lifecycle of pharmaceutical development including post market commitments for monitoring. The sensing system allows the collection of data on a variety of physiological parameters, including bioelectric data, to be collected over extended time periods in continuous or semi-continuous durations, or collected frequently for shorter durations. The data collected in this manner can then be used to build or augment a normative database, which can be utilized to develop, extend, adapt, and validate health indices. Comparison of new data against historical data and health indices permits improved pharmacovigilance and/or pharmacoepidemiologic safety signal assessment and interpretation.

Additional objects, features and advantages of the present invention will become more readily apparent from the following detailed description of a preferred embodiment when taken in conjunction with the drawings wherein like reference numerals refer to corresponding parts in the several views.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a simplified diagram of the physiological sensing system of the present invention; and

Figure 2 is a block diagram of a typical monitoring and analysis event utilizing the sensing system of Figure 1.

DETAILED DESCRIPTION OF THE PREFERRED

EMBODIMENT

With initial reference to Figure 1, a physiological sensing system is generally indicated at 10. Sensing system 10 includes a multi-sensor support article 20, a base station 30 and a data analysis unit 40. Support article 20 can be a belt as shown in Figure 1 , or can be any other type of article worn by a test subject 55, such as a hat, a shirt or a headband, for example, or may be an object against which a test subject is supported. Support article 20 preferably includes a plurality of sensors 60, 61 and 62, fasteners 70 and 71, an integrated power unit 80 and an integrated support electronics unit 90. Power unit 80 is preferably rechargeable and is in communication with electronics unit 90 and sensors 60, 61, and 62 through connector 93. Fasteners 70 and 71 can be any kind of standard fastener such as, for example, Velcro, snaps, or hook and eyelet fasteners. Additionally, support article 20 may include an alarm 95 to provide test subject 55 with a reminder or give notice of a particular event. Electronics unit 90 preferably includes a data processor and a communications device, such as a receiver/transmitter (not shown), and can be programmed to sample and/or transmit data on a set schedule. Further, electronics unit 90 preferably provides for local signal analysis and processing, including filtering, power regulating and/or artifact reduction. Signal processing is well known in the art, so need not be discussed in detail. It should be understood that any standard methods for signal processing and analysis may be utilized with the present invention.

Sensors 60, 61 and 62 can be any type of sensor necessary for gathering data on a particular physiological parameter from a test subject, but preferably, at least one of the sensors 60, 61 and 62 is a capacitive- type electrical sensor for obtaining biolelectric field signals such as electrocardiogram (ECG) data. Other sensors that could be utilized include, for example, accelerometers, temperature sensors, subject orientation sensors and/or galvanic skin response sensors. Although support article 20 is shown having three sensors (60, 61, and 62) it should be readily apparent that the number and type of sensors can be modified in order to provide a system user with the most pertinent physiological data for a particular monitoring event. That is, sensing system 10 can be customized to provide the most pertinent physiological data for a particular pharmaceutical monitoring event. Sensors 60, 61 and 62 communicate with power unit 80 and electronics units 90 via connector Base station 30 preferably includes a user interface 100, a data storage and processor 110 and a communications device 120, such as a receiver/transmitter, capable of communicating with support article 20. Data processor 110 may provide local data signal analysis and processing, including filtering, power regulating and/or artifact reduction. It should be apparent that additional processors or software could also be utilized by base station 30, depending on the application of sensing system 10. Data may be transferred between base station 30 and support article 20 using, for example, wireless (preferred), fixed cable, telephone, or internet transmissions as indicated at 125. Furthermore, base station 30 preferably includes a power interface device 130 adapted to connect to and recharge power unit 80 on support article 20. Base station 30 adds flexibility to sensing system 10, allowing a test subject to collect data from home, for example, over an extended period of time.

Analysis unit 40 includes a data processor 140 and a communications device 150 capable of communicating with base station 30, as indicated at 155, or directly with support article 20 as indicated at 160. It should be apparent that additional processors or software could also be utilized by analysis unit 40, depending on the application of sensing system 10.

With reference to Figure 2, the process by which sensing system 10 is best utilized for a particular pharmaceutical study will now be described. Initially, a user defines a population from which he/she wishes to collect physiological data, and then selects individual test subjects 55 to participate in the study as indicated at 300. The user also defines safety standards for the particular pharmaceutical test he/she wishes to conduct as indicated at 310. These safety standards preferably include safe ranges for QT prolongation and HRV. A support article, such as support article 20a is provided to each test subject 55 participating in the pharmaceutical monitoring event. Support article 20a is programmed to collect data from a test subject 55 at desired times (frequency) and for a desired duration (ex. 1 hour per day, 7 days per week) as indicated at 320. In preferred embodiments, data is collected during periods of low HRV and/or the QT data is classified based on a test subject's HRV. In any case, the data collection or monitoring event can occur on a continuous or semi-continuous basis, or may occur on a frequent basis for a shorter duration. In most cases, data will be collected over an extended period of time, usually greater than thirty (30) days. Alarm 95 is preferably set to an "on" mode, where it can be activated, for example, in the situation where data collected from support article 20a indicate an unsafe condition for test subj ect 55.

Next, support article 20a is placed in contact with test subject 55, such that sensors 60a and 61a on support article 20a are positioned in proper physical orientation with respect to test subject 55 to allow collection of data from the sensors. As previously discussed, the use of capacitive-type sensors eliminates the need for conductive gels, adhesives, or the like, and eliminates the need for constant direct contact between sensors 60a, 61a and test subject 55. Physiological signal data 330 generated by test subject 55 are gathered by sensors 60a, 61a and support electronics 90 provide initial signal analysis and processing as indicated at 340. In the preferred embodiment this processing includes filtering, compression, initial analysis (to indicate the successful/unsuccessful collection of data), data storage and transmission of data to base station 30 or analysis unit 40. Data transferred at 350 can be directed to base station 30 for further analysis and/or storage before being transmitted to analysis unit 40. Regardless, test data is eventually transferred to analysis unit 40, as indicated at 350, where analysis unit 40 utilizes the test data to create or augment a normative data base 360. Further, analysis unit 40 compares and analyzes test subject data, preferably utilizing normative database 360, data mining, and other indices 370 which can be refined and adapted for a specific monitoring event as indicated at 365. These indices can include specific percent change in QT duration, shift in heart rate variability, etc. In the preferred embodiment, analysis unit 40 utilizes data from multiple sensors for the development, extension, adaptation, and/or validation of cardiac pathology predictive indices. The comparison of new test subject data against normative data and indices can be utilized for identification, prediction, and tracking of health and/or disease states as they are affected by the use of a pharmaceutical(s). In particular, analysis unit 40 allows for the comparison, assessment, and interpretation of cardiac safety signals defined by the pharmacovigilance or pharmacoepidemiological guidelines. Analysis unit 40 may utilize one or more advanced mathematical processing schemes such as neural networks, Hidden Markov Models, among other pattern recognition and feature extraction methods known in the art. The raw data obtained with the system are processed by known algorithms for obtaining useful physiological data, such as QT/QTc and heart rate variability information. Output 380 is generated by analysis unit 40 based on processed and analyzed test data, and can be in the form of FDA, Pharmaceutical Developer, pharmacovigilance, or Updated Indices reports, to name a few. In the preferred embodiment, physiological signal data 330 is gathered by article 20a over an extended period of greater than 30 days and includes an ECG signal. The raw signal data 330 obtained is processed by base station 30 and/or analysis unit 40 utilizing known algorithms for obtaining QT/QTc and heart rate variability information. The resulting long-term QT/QTc values are more reflective of actual drug-induces changes than those obtained by short-term monitoring events and can be utilized to build or update a normative database, which in turn can be used to develop, extend, adapt and validate health indices.

The method for collecting and analyzing physiological parameter data of a test subject for pharmaceutical monitoring comprises initially defining a test population and selecting one test subject for a pharmaceutical monitoring event. A capacitive-type sensor is positioned on a support article in proper physical orientation on the test subject for collecting physiological parameter data from the test subject, the support article including an electronics unit in communications with the sensor, and a power unit in communication with the electronics unit and the sensor. The electronics unit is programmed to collect physiological data from the sensor for a set frequency and duration, wherein the electronics unit is programmed to collect data on a first physiological parameter on a continuous basis, a semi-continuous or a high frequency but short duration basis. Data is collected and initial data processing is preformed on the first physiological parameter data. Also the first physiological parameter data is analyzed based on a normative data set; and a report is generated based the first physiological parameter data. This overall system provides for the measurement, monitoring, storage and transmission of physiological data to permit improved pharmacovigilance and/or pharmacoepidemiologic safety signal assessment and interpretation. While described with reference to a preferred embodiment of the invention, it should be readily understood that various changes and/or modifications can be made to the invention without departing from the spirit thereof. For example, the actual circuitry and individual system components can take on various forms known in the art while being used for the purposes described above. Such forms might include sensor embodiments comprising a garment with integrated sensors; an object against which an individual is adapted to be supported; and data transfer methods such as USB, Ethernet, wireless, telephonic (including both landline and cellular) or other means. In addition, although the most preferred form of the invention employs a support unit, a base station and an analysis unit, it should be understood that other arrangements could be employed. For instance, the support unit could directly communicate with the analysis unit, either on a local or remote basis. Therefore, the base station, which is considered to be particularly advantageous as enabling the support unit to be considerably reduced in size, weight and the like, need not be present or could simply be incorporated in the support unit and even worn on the body, e.g., on an arm, around the waist or the like. In any case, when employed, the base station is preferably in the immediate vicinity of the test subject, wherein the analysis unit may or may not be physically near the test subject. In general, the invention is only intended to be limited by the scope of the following claims.

Claims

I/WE CLAIM:

1. A sensing system for monitoring of physiological parameters of a test subject given a pharmaceutical during pharmaceutical development, the sensing system comprising: a support article including a capacitive-type sensor for sensing and providing data on a first physiological parameter of the test subject, an electronics unit in communication with the sensor, and a power unit electrically connected to the electronics unit and the sensor, the support article being adapted to position the sensor in proper physical orientation on the test subject for collecting the data on the first physiological parameter; and an analysis unit including a data processor and a communication device, the analysis unit being adapted to communicate with the support article to receive data on the first physiological parameter and to analyze the first physiological parameter data based on a normative data set, the analysis unit further adapted to generate a report based on the analyzed first physiological parameter data.

2. The sensing system of claim 1, further comprising: a base station including a user interface, a data processor and a communication device, the base station being adapted to communicate with the support article to receive data on the first physiological parameter.

3. The sensing system of claim 2, wherein the communication device of the base station and the communication device of the analysis unit are wirelessly connected.

4. The sensing system of claim 1, further comprising: a second sensor for sensing and providing data on a second physiological parameter, wherein the analysis unit is further adapted to receive data on the second physiological parameter and to analyze the second physiological parameter data based on the normative data set, and wherein the report is based on the analyzed second physiological parameter data.

5. The sensing system of claim 1, further comprising: an alarm carried by the support article.

6. The sensing system of claim 1, wherein the electronics unit provides initial processing of the first physiological parameter data, with the initial processing including filtering, power regulation and artifact reduction.

7. The sensing system of claim 1, wherein the report is an electrocardiogram.

8. The sensing system of claim 1 , wherein the power unit is rechargeable.

9. The sensing system of claim 8, further comprising: a base station including a user interface, a data processor and a communication device, the base station being adapted to communicate with the support article to receive data on the first physiological parameter, said base station including a power interface device adapted to connect to and recharge the power unit.

10. A method for collecting and analyzing physiological parameter data of a test subject for pharmaceutical monitoring, the method comprising: defining a test population; selecting the test subject from the test population for a pharmaceutical monitoring event; giving the test subject a pharmaceutical; positioning a support article having at least one capacitive-type sensor in proper physical orientation on the test subject for collecting physiological parameter data from the test subject, the support article including an electronics unit in communications with the sensor, and a power unit in communication with the electronics unit and the sensor; collecting data on the first physiological parameter based on a programming of the electronics unit to collect physiological data from the sensor at a set frequency and duration; performing initial data processing on the first physiological parameter data; and generating a report based utilizing the first physiological parameter data.

11. The method of claim 10, wherein the electronics unit is programmed to collect data on a first physiological parameter on a continuous, semi-continuous or high frequency basis.

12. The method of claim 10₅ further comprising; transmitting the first physiological parameter data from the support article to an analysis unit having a data processor; performing secondary data processing on the first physiological parameter data; and analyzing the first physiological parameter data based on a normative data set.

13. The method of claim 12, further comprising: initially transmitting the first physiological parameter data to a base station having a data processor and a communications device; and transmitting the first physiological parameter data from the base station to the analysis unit.

14. The method of claim 10, further comprising: programming the electronics unit to collect physiological data from the sensor over a period greater than 30 days.

15. The method of claim 10, further comprising: measuring effects of the pharmaceutical on a QT interval of the test subject.

16. The method of claim 12, further comprising: positioning a second sensor on the support article in proper physical orientation with respect to the test subject for collecting second physiological parameter data from the test subject; collecting data on the second physiological parameter; performing initial data processing on the second physiological parameter data; transmitting the second physiological parameter data from the support article to the analysis unit; performing secondary data processing on the second physiological parameter data; and analyzing the second physiological parameter data based on a normative data set, wherein the report is generated utilizing both the first physiological parameter data and the second physiological parameter data.

17. The method of claim 16, further comprising: transmitting the second physiological parameter data from the support article to a base station and from the base station to the analysis unit.

18. The method of claim 16, wherein the second physiological parameter is selected from the group consisting of temperature, test subject orientation, acceleration, galvanic skin response and heart rate.

19. The method of claim 12, further comprising: re-charging the power unit of the support article.

20. The method of claim 19, further comprising: initially transmitting the first physiological parameter data to a base station and then from the base station to the analysis unit; and re-charging the power unit from the base station.