12-Lead ECG Systems in Clinical Trials

23rd November 2018 (Last Updated August 9th, 2019 11:35)

Ruey-Kang Chang, MD, MPH, Founder and CEO, QT Medical, reviews advances made in the development of electrocardiograms

12-Lead ECG Systems in Clinical Trials

Cardiac toxicity is one of the primary reasons pharmaceutical products were withdrawn from the market in the past. The International Conference on Harmonization (ICH) provided the guidelines for rigorous testing of a compound in development for its potential of prolonging the QT interval on electrocardiogram (ECG). Since the implementation of this guidance known as the ICH E14 in 2005, there has been no post-market withdrawal of a drug due to its torsadogenic toxicity.

To test a compound for its potential for prolonging the QT interval, careful assessment of ECG parameters in a standalone trial known as thorough QT study (TQT study) is required. A well-controlled TQT study may involve a large number of study subjects and the need for frequent ECG testing. In recent years, the clinical trial industry is moving towards decentralization, virtual, and siteless study designs.1  Using a conventional ECG may become increasingly burdensome for many sponsors and CROs. In this report, I review the current ECG systems used in clinical trials and the new ECG technologies enabling siteless clinical trials that need ECG testing.

Conventional 12-lead ECG Systems

Conventional 12-lead ECG systems typically have a physical keyboard, an LCD screen or touchscreen, and a printer. Examples of the systems include GE MAC 5000, Philips PageWriter TC70, and Mortara BUR280. In the last 10-15 years, digital ECG systems emerged, which allows the ECG to connect to a laptop computer, thus eliminating the need for a keyboard and LCD screen, and makes the ECG systems much more compact and portable. Examples of these ECG systems are Nasiff Cardiocard, Welch Allyn CP200 and MidMark IQecg.

New generation ECGs can now use Bluetooth connection to aChang_Fig 1 computer or tablet, further eliminating the need for a USB cable connection.   Many use smart mobile devices, such as phones and tablets in iOS or Android, and are cloud-connected for centralized management in a HIPAA compliant cloud server. Examples of these ECGs are InvisionHeart and Spaulding iQ Electrocardiograph (Fig. 1). Despite the improvements in the ECG recorder itself, one commonality of all the conventional ECG systems is that the electrodes and leads cables—they are all 10 individual electrodes and 10 cables (RA, LA, RL, LL, V1, V2, V3, V4, V5 and V6).

As the electrodes and cables make the procedures of conducting a 12-lead ECG test complicated, conventional ECGs require a trained technician or nurse to do the test. As a result, acquiring a 12-lead ECG using conventional ECG systems typically involves scheduling the study subject to a site for a technician to do the test, or a technician or nurse visiting the subject’s home. While conventional ECG systems had served the TQT studies well in the past, there are many limitations for their use in the increasing demands of the industry to speed up the trials and save cost by moving the tests to subjects’ homes.

New 12-lead ECG for Home Use

These new ECG systems are digital, wireless, compact and portable. They use smart mobile devices, such as phones and tablets in iOS or Android, and are cloud-connected for centralized management. More importantly, the electrodes and cables are simplified to allow laypeople, such as study subjects or patients themselves, to conduct an ECG test without the need for a technician.Chang_Fig 2

It is this particular feature that enables 12-lead ECG to be obtained at the subject’s home and reduces or eliminates site visits in clinical trials. For some of the study protocols that require periodic, multiple ECG testing of the subjects during the course of their study participation, considering home ECG as an option can enhance the subject’s adherence to the study, and potentially speed up subject recruitment and study progress.

There are currently two ECG systems on the market that can be used by laypeople without a technician.  SmartHeart by SHL Telemedicine (Fig. 2) was cleared by CE Mark first and then by the U.S. FDA in 2012.  SmartHeart has been in use by patients to transmit 12-lead ECG from homes to doctors. However, its use in clinical trials is limited for the following reasons:

  • Dry electrodes—Dry electrodes make acquiring ECG signals variable depending on the skin condition. Without adhesives, attachment to skin for men with a hairy chest and women with large breasts can be challenging
  • Non-standard electrode placements—The limb leads placements do not follow the standard placements, and the chest leads (V1-V6) may not be accurately placed
  • Sampling rate—The sampling rate is not stated in the specifications, but is likely 500 Hz or lower, may not be considered the medical standard by AHA Guidelines, thus may not be used for the TQT study reporting to the FDA

The other ECG system that can be used without a technician is QT ECG (Fig. 3) by QT Medical. QT ECG was cleared by the FDA in May 2018 for laypeople use in homes or a non-acute care health care environment. The disposable electrode strip comes in four sizes for adults.

Chang_Fig 3

The electrodes use same material of the ECG electrodes used in the hospital— Ag senor, hydrogel, and biocompatible adhesives for medical use. The electrode placements follow standard placement by the AHA Guidelines, where the RA lead will be pulled to distal to the right shoulder, LA to distal to the left shoulder, and LL to distal to the left hip joint. The sampling rate is 1000 Hz. The apps to be used with QT ECG are available for iOS and Android platforms, for both phones and tablets.

The Table below compares the specifications of the Spaulding ECG, SmartHeart and QT ECG.

Chang_Fig 4

Reference

  1. Smalley E. Clinical trials go virtual, big pharma dives in. Nature Biotechnology. 2018;36:561.