a primer on collecting cardiac safety data during drug development · 2020. 5. 12. · a primer on...

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A PRIMER ON COLLECTING CARDIAC SAFETY DATA DURING DRUG DEVELOPMENT

Robert Kleiman, MD

A Primer on Collecting Cardiac Safety During Drug Development

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TABLE OF CONTENTS BACKGROUND – WHY WE COLLECT ECGS DURING DRUG DEVELOPMENT........ 3

Modern ECG Machines ......................................................................................................... 5 Newer Varieties of ECG Machines........................................................................................ 6

WHAT THE ECG CAN TELL US DURING CLINICAL TRIALS ...................................... 7 Can I Rely on ECG Machine Measurements & Interpretation? ........................................... 9 Can I Rely on the Site ECG Evaluation? ............................................................................ 11

ARE SITE COLLECTED PAPER ECGS EQUIVALENT TO DIGITALLY COLLECTED ECGS? .......................................................................................................................... 13

CONTINUOUS ECG RECORDING ............................................................................... 15 Uses of Continuous ECG Recordings in Clinical Trials ................................................... 17 Use of Continuous ECG Recordings to Generate 12 Lead ECGs .................................... 17

SUMMARY .................................................................................................................... 19


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BACKGROUND – WHY WE COLLECT ECGS DURING DRUG DEVELOPMENT Regulatory authorities have required that cardiac safety data be collected during all clinical phases of the development of a new drug – whether the drug is targeted at a cardiac or non-cardiac indication. But what exactly does this mean? Just what sort of data is required? This discussion will focus on the types of cardiac safety data which the FDA and other regulatory authorities typically expect to be collected during drug development.

The majority of cardiac safety data which is collected during clinical trials is electrocardiographic data – typically involving standard 12 lead ECGs, but often including longer duration continuous ECG recordings often referred to as Holter recordings. The emphasis on capturing ECGs during drug development is simple to understand – ECGs are safe, painless, quick, and inexpensive. Furthermore, the devices which are used to collect 12 lead ECGs are relatively inexpensive, portable, and widely available throughout the world, and the paper ECGs which are printed out by such devices are immediately available for review by the local sites. Nearly all physicians have at least some training and familiarity with 12 lead ECGs. ECGs are commonly used in clinical practice unrelated to drug development, and ECGs are therefore familiar to most patients and clinical sites.

A bit of terminology - the terms “ECG” and “EKG” are used interchangeably in the medical community. The electrocardiogram was developed by a number of investigators, but the development of the electrocardiogram is largely credited to Willem Einthoven, whose work laid the groundwork for much of our current practices. Einthoven (who won the Nobel Prize for Medicine in 1924 for his efforts) lived in Germany, and in German, the term for “elektrokardiogam” is shortened to EKG. In English, the equivalent term is “electrocardiogram”, and hence ECG.

ECGs were initially collected one lead at a time, and in many different formats, but currently nearly all ECGs are collected in the 12-lead format with 4 electrodes attached to the limbs (or torso) and 6 electrodes attached to the anterior chest wall. Each “lead” is actually the collection of the voltage difference between the two electrodes used; some of the “leads” are simple recordings of the voltage difference between two electrodes. For example, “Lead I” is a recording of the voltage difference between the electrodes attached to the right arm and left arm. Other leads refer to the difference in voltage between one of the physical electrodes and a “composite” lead which is calculated from the sum of several of the limb leads. The “augmented” leads aVR, aVL and aVF are recordings derived from the other limb leads. The


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unipolar precordial leads V1 through V6 are recordings between the precordial electrodes and a composite of the limb electrodes.

The important concept here is that the ECG leads really are just measurements of the voltage difference between different points on the skin. They are not really direct measurements of the electrical activity of the heart – they record signals from within the heart, but also from the electrical activity of the musculature, the motion of the chest wall, and external electrical interference. Nevertheless, the majority of the signal which we view in an ECG is related to the electrical activity of the heart, and this is why the ECG is such a useful tool. It is helpful to think of the 12 leads as being views of the electrical activity of the heart from 12 different views, from slightly different positions and angles on the human body.

Despite the mundane origin of the 12 lead ECG signals – measurements of the voltage difference between sets of points on the skin – the ECG is a remarkably valuable tool, which can let us examine many aspects of the heart. The ECG allows evaluation of the heart’s electrical activity, and this allows examination of the area which is driving the heartbeat (the rhythm) as well as the pattern of spread of electrical activity across the heart (conduction). The ECG also allows an evaluation of the overall pattern of electrical activation of the heart, as well as the return of cardiac electrical activity to normal (repolarization). Besides allowing us to evaluate these electrical phenomena in the heart, the ECG also allows us to assess many physical cardiac parameters – the size and thickness of the cardiac chambers, and the presence of myocardial ischemia or of myocardial infarctions. For a noninvasive, painless and inexpensive tool, the ECG is remarkably useful. It is little wonder that the ECG has found such wide use in clinical practice. ECGs are used to evaluate patients complaining of symptoms of lightheadedness, shortness of breath, chest discomfort, and for general screening of asymptomatic patients for possible cardiac problems.

During clinical drug development, ECGs are commonly used for several different reasons. First and foremost, ECGs are collected during clinical trials in order to insure patient safety. During a clinical trial, a patient may develop cardiac issues due to underlying cardiac disease or preexistent risk factors, and we are obligated to help patients manage their ongoing medical problems. In addition, there is always a concern that the investigational product, even if it has no known cardiac issues, might have as yet unknown cardiac side effects. These can only be detected if we maintain careful surveillance of the cardiac status of all patients in our clinical trials. As a low cost, noninvasive, painless procedure, the ECG is an obvious tool to utilize.


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It is therefore standard to collect ECGs during many clinical trials. These ECGs will be used both to monitor healthy volunteers or patients for cardiac issues unrelated to the clinical trial, as well as to detect any cardiac issues which are directly related to the investigational agent. The results of the ECG may be used at the investigator’s site to manage the care of the subject, and will also be used in the program wide evaluation of the cardiac effects of the new agent.

Modern ECG Machines Modern ECG machines come in a variety of shapes and sizes, ranging from handheld devices the size of a mobile phone to large cart-based machines with flat panel displays. Most devices share several common characteristics. All are connected to the patient with a set of electrodes which are placed on the patient’s arms and legs (or torso) and on the anterior chest wall. Most ECG machines are designed to collect 12 simultaneous leads, requiring 10 electrodes. The ECG machine itself contains the amplifiers and electronics to record the signals detected by the electrodes, and the ECG machine records this as a digital file. Most modern ECG machines contain a printer which allows a paper ECG to be printed at the site, and have the capability to store and transmit the electronic ECG files (via Bluetooth, USB connection, or wirelessly). Figure 1 shows an example of the most common format to display a 12 lead ECG. In the upper left corner the ECG machine algorithm determined measurements are shown, with the ECG machine algorithmic interpretation at the top, center. Below is a pink grid, with the 12 ECG leads displayed in 2.5 second segments. The fourth row of ECG waveforms shows a continuous rhythm strip recorded from lead II. Notice that this is synchronized with the leads above it – this is an example of an ECG for which each set of 3 leads represents 2.5 seconds of different data. The first 3 leads shown (I, II and III) represent the first 2.5 seconds of the recording; the second group of 3 (aVR, aVL and aVF) represent the next 2.5 seconds, and so on.


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Figure 1. Typical format of a 12 lead ECG with rhythm strip printed by an ECG machine

Newer Varieties of ECG Machines The traditional 12 lead ECG machine is typically a bulky device about the size of a desktop computer, and includes a built-in printer which typically prints on 8 1/2x11-inch paper. A variety of new, often smaller form factor ECG machines have been developed in the past decade, many of them specifically for use in clinical trials. The larger, standard size ECG machines often are mounted on a cart in order to improve mobility. Some newer 12 lead ECG machines retain a printer, but use 4x11-inch paper. The use of the smaller format paper significantly reduces the size and weight of the ECG machine, making it easier to transport and store. Even smaller 12 lead ECG machines are available which dispense with a built-in printer, and which may be as small as a thick slice of bread. These devices typically transmit the collected ECG to a local computer or to a web portal, from which the ECG may be printed by the site, as well as transmitted to a central lab or storage repository.


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The ECG machines which are typically used in clinical trials differ in several ways from the devices which are used in clinical practice. First, in order to be useful in clinical trials, an ECG machine must be relatively easy to use (since many sites will not routinely collect ECGs and will not be very experienced with the device), but must be capable of storing subject demographic data allowing identification of the site, investigator, protocol, subject identifiers, and visit information. In addition, the ECG machines used in clinical trials generally must be capable of transmitting the digital ECG file to a central core lab or to another central repository. This transmission may occur via a number of conduits, including telephone modem, blue tooth, LAN, USB or wireless transmission. Many modern ECG machines include multiple transmission options, which can be useful depending on the country in which an investigational site is located, the type of phone line and internet access available, and whether the site has access to a computer and is permitted to install external software for ECG acquisition.

WHAT THE ECG CAN TELL US DURING CLINICAL TRIALS Modern 12 lead ECGs are used to evaluate a number of different cardiac parameters. The evaluation of a 12 lead ECG includes the measurement of a number of parameters which may be measured on a single beat (PR interval, QRS duration and QT interval are the most common) or across a number of beats (RR interval or heart rate). In addition, a morphologic evaluation is performed based on a review of the ECG waveforms and a process of pattern recognition of standard patterns which have been generally accepted by the electrocardiography community.

The evaluation can tell us a great deal about the cardiac rhythm, conduction through the atria and ventricles, chamber size, and the presence of myocardial ischemia and myocardial infarction. The rules for using the ECG to diagnose these cardiac conditions have varying degrees of sensitivity and specificity. For example, most of the ECG criteria for diagnosing left ventricular hypertrophy have sensitivity and specificity which are only 30-50%.

Nevertheless, the ECG still remains a useful tool because it is noninvasive and inexpensive, in contrast to many of the newer, much more precise cardiovascular tests which are now available.


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In general, the cardiologist review of an ECG will evaluate the following components:

• Confirmation that the interval duration measurements (HR, PR, QRS, QT) are correct: drugs may alter any or all of these:

o PR Interval: time from beginning of atrial activation through initial activation of ventricles, including:

o Conduction from sinus node through atria

o Conduction through the AV node

o Conduction through the Bundle of His

o QRS Interval: duration of ventricular depolarization

o QT Interval: duration of ventricular depolarization through complete ventricular repolarization

o RR Interval: interval between two QRS complexes

§ RR = 60,000/HR

o QTc Interval: QT interval corrected for heart rate

Figure 2. A single ECG complex consists of a P wave, QRS complex, and T wave (often with a small U wave – not shown).

• Evaluation of the cardiac rhythm: drugs may produce atrial or ventricular arrhythmias, or suppress the normal intrinsic cardiac rhythm (known as sinus rhythm)


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• Evaluation of atrioventricular conduction: drugs may produce slowing of AV conduction, or even produce AV block (heart block)

• Evaluation of inter- or intra-ventricular conduction pattern: drugs may delay conduction within the ventricles, producing altered QRS morphology

• Evaluation of ST segment changes: drugs may produce shifts in the ST segment due to myocardial ischemia or pericardial inflammation

• Evaluation of T waves: drugs may produce changes in the morphology or duration of T waves

• Presence of abnormal U waves: drugs which alter repolarization often produce bizarre, enlarged U waves

• Presence or absence of evidence of myocardial infarction: drugs may produce increased rates of myocardial infarction due to prothrombotic or direct vascular effects

• Evaluation of chamber size: drugs may produce enlargement of the atria or ventricles

Can I Rely on ECG Machine Measurements & Interpretation? Modern 12 lead ECG machines generally provide a printout of the 12 lead ECG which often includes a set of measurements and an interpretation generated by the ECG machine software. These measurements and interpretations are based on algorithms developed by the ECG machine manufacturer. As a general rule, the ECG machine measurements and interpretations are adequate for use by the personnel at the site for a very rough first glance at immediate patient safety, but a review by an experienced electrocardiographer is required for a proper interpretation, and measurement by a centralized core lab is required for the collection of high precision data for regulatory submission. The ECG algorithms are relatively poor at interpretation – they tend to overcall many abnormalities, and have very high rates of false positives. The ECG machine algorithms are somewhat better at performing measurements, but all algorithms are prone to errors. Furthermore, the lower the quality of the recording, and the more abnormal the ECG, the higher the likelihood that the ECG machine measurements will be incorrect – most notably for the QT and QTc measurements. Figure 2 shows an example of a set of ECG machine measurements (shown with red vertical calipers) in which the PR and QRS measurements are correct, but the QT is grossly undermeasured (the true T wave offset is marked with the black arrow). This was a very good quality ECG with a completely normal appearance and with normal T waves, but the algorithm simply could not recognize the T wave offset. Similarly, Figure 3 illustrates an example of a set of ECG machine measurements where the QT interval is grossly overestimated. In this case, it is clear that the ECG machine algorithm misinterpreted the end of the U wave as the T wave offset.


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Figure 3. ECG machine measurement grossly underestimating QT interval

Figure 4. ECG machine measurement grossly overestimating QT interval


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Can I Rely on the Site ECG Evaluation? Since the site investigator is obligated to review the ECG printed by the ECG machine to look for any immediate safety issues, it’s common to ask whether the site interpretation and measurements can be used, or whether centralization of the ECG measurements and evaluation are really necessary. A full discussion of the value of ECG centralization in clinical trials is beyond the scope of this review, but a few points are worth discussing.

First, consider the ECG measurements. Most physicians do not read ECGs regularly, and many practice in specialties or subspecialties in which ECGs are rarely collected. Many very highly skilled MDs have little familiarity with ECG evaluation, and particularly with ECG measurements. It is therefore very common for sites to simply copy the ECG machine measurements into the CRF rather than have someone manually perform the measurements. As discussed, ECG machine measurements are really not ideal for data which will be submitted for regulatory review. Furthermore, very few physicians, including most cardiologists, are very experienced at precise ECG measurements or evaluation of the QT interval. Dr. Sami Viskin published the very interesting results of an experiment he performed a few years ago. Four ECGs – two with a normal QTc interval, and two with a prolonged QTc, were sent to 900 physicians, including cardiologists, non-cardiologists, and arrhythmia specialists (cardiac electrophysiologists). The non-cardiologists and cardiologists correctly measured the QTc for less than 50% of the ECGs, and only 25% of the non-cardiologists and cardiologists correctly identified the correct diagnosis for all four ECGs! It is therefore very uncommon to encounter a site where an expert electrocardiographer has the training and sophisticated equipment necessary to perform very precise ECG measurements. In order to obtain a high-quality set of measurements for use in the statistical analyses which will accompany a regulatory submission, it is essential to use a central core lab to perform the ECG measurements in a uniform, extremely precise fashion. This is the data that the regulators will use to determine if a drug has a QT liability – a critical milepost for any new drug. The ICH E14 Guidance for Industry goes so far as to specifically state that for the “thorough QT/QTc study”, a sponsor should use measurements performed by “a few skilled readers (whether or not assisted by computer) operating from a centralized ECG laboratory”.

Next, let’s consider the interpretation of the ECG morphologic finds (rhythm, conduction, etc.). Again, most physicians are not expert electrocardiographers. When a site is required to report the findings and the site physician does not have extensive ECG experience, the site chose to simply report the ECG machine interpretation, with all of the attendant pitfalls (ECG machine interpretation algorithms are not very good). Alternatively, the site may ask a local cardiologist to review the ECG. While the local cardiologist may be quite capable of interpreting the ECG, it


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is likely that the use of multiple different cardiologists at multiple different sites will all report similar findings in slightly different ways. In clinical practice, this is rarely critical, as the individual ECG reports will be read by the appropriate clinicians, who can interpret the report themselves, or ask the reviewing cardiologist for their opinion. In clinical trials, however, slight variations in ECG reporting style will lead to a database full of inconsistencies which make data analysis impossible. For instance, consider the following scenario: during a Phase III trial of a new antidiabetic agent, a patient had 5 ECGs recorded at half yearly intervals and read locally, with reports as shown in Figure 4.

Figure 5. Site Reports of ECGs collected at 6-month intervals for a single patient

When this data was reviewed in the study database, it was interpreted as showing a new Inferior myocardial infarction (MI) between Visits 4 and 5, when the term “Inferior MI” was first used without any modifiers. The sponsor’s medical team was suspicious that there hadn’t really been a new cardiac event. A review of all 5 ECGs by an independent cardiologist consultant hired by the sponsor confirmed that all 5 ECGs were nearly identical and showed evidence of a remote inferior myocardial infarction (MI) which had not changed during the course of the trial.

The issue with decentralized, local ECG reading is simply that having a large number of different ECG readers who have different training, different reading styles, and who report similar findings slightly differently will lead to a database that is so noisy as to be useless for detecting, or excluding, new cardiac signals.

In contrast, when ECGs are reviewed by a central ECG core lab, all of the ECGs are reviewed by a small group of cardiologists who are trained to report findings in the same fashion, with pre-specified interpretation guidelines and a standardized set of terms for reporting. This leads to a far cleaner, far more easily interpretable database.


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ARE SITE COLLECTED PAPER ECGS EQUIVALENT TO DIGITALLY COLLECTED ECGS? Another decision which must be made when planning the cardiac safety aspects of a clinical trial relates to whether to collect ECGs using site owned equipment, or utilize ECG machines provided by a centralized lab. The advantages to having the sites be responsible for the ECG machine equipment are obvious – there will be no expense to the sponsor for rental of ECG machines, training the sites in the use of the ECG machines, or need to track and ultimately insure the return of the equipment. There are significant disadvantages, though, to the use of site owned equipment. First, different sites will use ECG machines from different manufacturers, which may have many different models and different versions of software. Any data collected in this manner will inevitably contain measurements and interpretations which are inconsistent. If this data is used by the sites for enrollment and dosing decisions, let alone to create the ECG database, there will inevitably be inconsistencies between the data collected from different devices and different versions of the same device software. Another issue arises when the data collected at the site needs to be entered into the CRFs – the issue of data entry errors, as well as the need for additional monitoring by CRAs.

From a scientific standpoint, an even greater disadvantage to the use of site owned machines and the collection of ECGs printed from the ECG machines, even if they are sent to a centralized lab for analysis, concerns the quality of the ECG recordings. Different ECG machines will generate printouts in a variety of different formats, and use a variety of different types of paper. Some ECG machines print on thermal paper, and produce ECG tracings which fade over a period of months or years. However, even the highest quality ECG printed from an ECG machine will have far lower fidelity than an ECG collected and stored digitally. All modern ECGs machines record digitally, typically with sampling rates of 500-1000 Hz. Most will record a full 10 seconds of each of the 12 leads, and store this full recording in a format which is proprietary to the ECG machine manufacturer. This digital ECG file can be transmitted to a central repository for storage, or can be sent to a centralized lab for processing. In contrast, an ECG collected by an ECG machine and then printed at the site starts out with a full 10 seconds of each lead recorded at a very high sampling rate, but then prints this file out on a sheet of paper using an ink pen, inkjet, thermal printer or laser printer. The fidelity immediately drops significantly – the width of the ink line may be as wide as 5-10 ms! In addition, most ECGs are printed in the “3x4” format displayed in Figure 1, which displays only 2.5 seconds of each lead, and generally a single 10 second strip from a single lead (some ECG machines can be configured to print in different formats, allowing 2-3 long rhythm strips, or even 10 seconds of each lead, printed 6 leads to a page). A 2.5 second strip will be limited in the number of beats


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which are displayed – for a heart rate of 60 bpm, the ECG will display only 2-3 complexes per lead.

If this paper ECG is sent to a centralized lab for evaluation, the central lab may perform measurements on the paper ECG, or may scan and then digitize the ECG. This process will produce a digital ECG file, which can be manipulated electronically on-screen, but only at the expense of even further degradation of the ECG fidelity. The process of scanning, and the additional process of digitization, inevitably results in the further loss of data – just as if you photocopy a photograph again and again it becomes less and less sharp.

In contrast, when the sites utilize ECG devices provided by the central lab or by a CRO, all will utilize the same model and version device, eliminating the inconsistencies in the immediate data reviewed by the site, and allowing for electronic submission of the digital file to the core lab for processing. In this scenario, the core lab will receive the full, unedited, uncorrupted file with 10 seconds of each lead, and with high fidelity recordings. Figure 5 shows an example of the same ECG displayed as a digital file, as a scanned paper image, and as a digitized version of the scanned image.


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A. B.

C.

Figure 6. Three versions of the same ECG: A. Digital, B. Paper ECG, scanned, and C. Digitized version of paper ECG

CONTINUOUS ECG RECORDING The standard 12 lead ECG is typically 10 seconds in duration. This may be sufficient for detecting persistent abnormal findings, or for making a diagnosis during an acute event, but may not be very helpful for evaluation of events which occur infrequently or unpredictably. For instance, consider a patient who reports that he has palpitations which last for 5 seconds, and which occur 1-3 times per day. The likelihood of capturing one of these episodes on a routine 10 second ECG performed is less than 1 in 1000, based purely on raw statistics. However, a routine 10 second ECG performed in a physician’s office has an even lower chance of capturing one of these episodes, since we can pretty much guarantee that an ECG performed while the patient is not experiencing symptoms will not capture the event!


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Standard 12 lead ECGs therefore are not very useful for detecting infrequent events. This problem led to the development of methods for recording continuous ECG data. The first such method is what we now think of as cardiac telemetry, and which is used extensively in hospitals to continuously record an inpatient’s ECG and to trigger an alert to the hospital staff in the event of a severe rhythm disturbance. The second strategy, and the one that is commonly used in clinical drug development, is what has come to be known as Holter monitoring, named after Dr. Norman Holter, who pioneered the development of ambulatory continuous ECG recordings in the 1960s. The original Holter monitor recorded a single ECG lead on a reel to reel tape recorder, and was at least theoretically portable – the original design (shown in Figure 6) weighed 85 pounds and had to be carried in a large backpack!

A. B.

Figure 7. A. Dr. Normal Holter wearing the original 85 pound Holter device. B. Modern 12 lead digital Holter recorder (courtesy of Mortara Instruments)

Modern Holter recorders now record up to 12 leads, store the recordings on a flashcard rather than on reel to reel tape, and are the size of a pack of playing cards. The recorders may store from 24 to 72 hours on a single flashcard, and may record signals at 180-250 Hz (standard fidelity) or at 500-1000 Hz (high fidelity). Standard fidelity Holter recordings are typically used for the detection of disturbances of the cardiac rhythm or conduction (Holter arrhythmia analysis), while the high fidelity flashcards may be used for arrhythmia analysis as well as to allow the extraction of 12 lead ECGs for standard ECG measurement and interpretation.


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Uses of Continuous ECG Recordings in Clinical Trials Continuous ECG recording is used in clinical trials for several different purposes. First, as in clinical medicine, Holter recordings are very useful for detecting infrequent disturbances of cardiac rhythm or conduction which would not be detected with standard 10 second ECGs. It is common in clinical trials to perform a baseline 24-hour Holter recording, and then one or more 24 hour recordings while patients are receiving study medication in order to document an increase in atrial or ventricular premature complexes, atrial fibrillation, supraventricular or ventricular tachycardia, sinus pauses, or episodes of AV block. Holters are also excellent tools for characterizing a drug’s effects on heart rate, and allows us to understand how the effects on heart rate may wax and wane following each dose.

Unlike standard 12 lead ECGs, which can only be performed by a trained medical professional (usually in an office, clinic or hospital), Holter recorders can also be used on an outpatient basis. Typically a subject in a clinical trial will have the Holter hooked up at the investigator’s site in the morning, and will then be allowed to return home while wearing the Holter. The patient returns the Holter when the recording is completed, and the data is transferred to a centralized lab to be evaluated. The data is stored on a removable flashcard, which the site can either mail to the centralized lab, or transmit digitally via a web upload utility.

Once received by the centralized lab, the Holter data is downloaded into a Holter workstation, which has proprietary software provided by the Holter manufacturer which allows processing of the Holter. The Holter software can provide a full automated analysis, but this is not recommended because the Holter software may be unable to distinguish artifact from QRS complexes. It is therefore necessary for a technician or physician to manually edit the recording, and remove all artifact. The analyst will then evaluate the Holter for episodes of abnormal rhythm and conduction, and will capture representative strips of any such findings for the Holter report. The Holter report may be printed and provided to the site or sponsor, or may be posted electronically on a web portal.

Use of Continuous ECG Recordings to Generate 12 Lead ECGs Besides being used for arrhythmia analysis, continuous 12 lead recordings can also be used to extract 10 second strips which can then be processed exactly the same as a standard 12 lead ECG machine digital file. Although the electrodes used for a 12 lead continuous recording are generally shorter than those used with a standard ECG machine, and the limb leads are


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generally placed more centrally (rather than on the limbs), the recordings are in effect interchangeable, as shown in Figure 7. Formal analyses have also confirmed the measurements collected from Holter extracted ECGs are equivalent to the measurements collected with standard 12 lead ECG machines, which has led to the acceptance of ECG data collected with continuous recorders by the various regulatory agencies.

A. B. Figure 8. A. 12 lead ECG recorded from 12 lead ECG machine

B. 12 lead ECG extracted from a 12 lead continuous recorder at the same time Continuous 12 lead ECG recorders are generally used to collect ECGs for trials which require the collection of numerous ECGs at multiple timepoints during a single day. Common examples in which a continuous 12 lead ECG recorder would be used include Phase I studies, intensive QT studies, and Thorough QT/QTc Trials (TQTs). During a TQT, it is not uncommon to collect ECGs at 10-15 timepoints during a single day. In contrast, during late phase trials when only single ECGs are collected at each visit, it is more practical to use a more traditional ECG machine to capture 12 lead ECGs.

The use of continuous 12 lead ECG recorders has largely supplanted the use of standard ECG machines during trials requiring intense ECG collection (though standard 12 lead ECG machines may still be used to collect safety ECGs for immediate site review). There are a number of advantages to the collection of ECGs with a continuous 12 lead ECG recorder:


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• Reduced burden for the site and subject: with a standard ECG machine, the site may be required to hookup and unhook the ECG leads multiple times, and must record each ECG individual. With a continuous ECG recorder, only a single hookup is required, and no site efforts are required to record individual ECGs.

• Ability to acquire highest quality ECGs possible at each timepoint: with a standard ECG machine, the 10 seconds which are recorded are the 10 seconds which are available for processing. If there is artifact, or the heart rate has not been stable, there is no recourse. With a continuous 12 lead recorder, one typically establishes an extraction window of 2-3 minutes on either side of a nominal timepoint during which the required ECG(s) may be extracted. The central lab can then scan this 4-6 minute window and select the best 10 second ECG (or ECGs, when replicate ECGs are collected. Triplicate ECGs are commonly used in clinical trials; in this case, three 10 second ECGs would be extracted within the extraction window). The central lab is able to select 10 second ECGs which have minimal artifact and ectopy, and when the heart rate is most stable.

• Ability to obtain ECGs at additional unplanned timepoints: with a standard ECG machine, ECGs are collected only at the pre-specified timepoints. If analysis of trial data suggests that additional ECG timepoints would have been desirable, there is nothing that can be done (other than repeating the trial). In contrast, a continuous ECG recorder records from the time it is hooked up and activated until it is unhooked. Months or years later, if it becomes apparent that additional ECG timepoints would be useful, it is a trivial matter for the central lab to retrieve the stored continuous recordings and extract 12 lead ECGs at the additional, unplanned timepoints. This scenario occurs fairly regularly, as pharmacokinetic data and evaluation of the metabolites of a parent compound may lead to questions which were not anticipated at the time that the trial protocol was written.

SUMMARY 12-lead ECGs are collected in many clinical trials during drug development. A variety of different types of instruments for collecting ECGs are currently in use, including very small devices which can transmit an ECG directly to a computer or web portal, standard 12 lead ECG machines, and continuous 12 lead ECG recorders. The best device for use in a clinical trial depends on the mix of sites which will be involved, the specifics of the investigational agent, and the frequency and intensity of ECG collection. No matter what type of device is used for ECG collection, digitally acquired ECGs are far superior to paper ECGs printed directly from the ECG machine or from a computer printer. For the highest quality data, processing by a central core lab is also recommended.

ABOUT ERT ERT is a global data and technology company that minimizes uncertainty and risk in clinical trials so that customers can move ahead with confidence. With nearly 50 years of clinical and therapeutic experience, ERT balances knowledge of what works with a vision for what’s next, so we can adapt without compromising standards.

Powered by the company’s EXPERT® technology platform, ERT’s solutions enhance trial oversight, enable site optimization, increase patient engagement and measure the efficacy of new clinical treatments while ensuring patient safety. Since 2014, more than half of all FDA drug approvals came from ERT-supported studies. Pharma companies, biotechs and CROs have relied on ERT solutions in 10,000+ studies spanning more than three million patients to date. By identifying trial risks before they become problems, ERT enables customers to bring clinical treatments to patients quickly — and with confidence.

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