ecg assessment during tqt and early clinical studies

THIJS van IERSEL, MDSenior Director, Global Scientific Affairs

Early Development Services, PRA Health Sciences

E C G A S S E S S M E N T D U R I N G T Q T A N D E A R LY C L I N I C A L S T U D I E S

EXECUTIVE SUMMARY

Assessing the cardiovascular safety of novel compounds is an important clinical drug development objective for drugs with preclinical cardiovascular safety signals and agents for which a cardiovascular class effect is suspected. Consequently, for most compounds, regulatory authorities still expect to see a Thorough QT (TQT) study according to ICH-E14. PRA Health Sciences provides the expertise you need to optimize study design and execution for TQT studies and ECG assessments during early clinical development and in clinical pharmacology studies.

P R A H E A LT H S C I E N C E S

ECG Assessment During TQT and Early Clinical Studies 2

E X E C U T I O N O F T Q T S T U D I E S AT P R A

PRA uses Mortara ELI™ 250c electrocardiographs (Figure 1) and Mortara 12-lead telemetry transmitters (Figure 2 and Figure 3) to record high-quality digital 12-lead ECGs. These ECG recordings can be saved in FDA-compliant XML format and analyzed by ECG core labs, if needed. During TQT studies, 12-lead Holter equipment is often used, for which PRA has collaborated with many ECG core labs.

The attention to standardized execution of ECG measurements pays off in the achievement of quality data. Standard deviation for QTc (msec) in TQT studies performed by PRA varies between 7.5 msec and 8.4 msec. This rate compares well with data in the literature (Darpo, 2011)1.

Even though we have never had a TQT study that failed to show sensitivity in the moxifloxacin arm, we believe that rigorous standardization of the execution of TQT studies can improve the quality of ECG recordings even further and decrease the intrinsic variability of the QT interval. Therefore, PRA has a Working Instruction (WI) for procedures during TQT Studies. We have discussed aspects of this WI with several key opinion leaders in the field. The WI’s purpose is to help us conduct the ECG extraction in the most stringent way, reducing heart rate variability during the period of ECG extraction and variability in autonomous tone between ECG extraction days. All ECG monitoring staff at PRA is trained in these procedures.

PRA has performed many TQT studies in our Clinical Pharmacology Units (CPUs) in the US and The Netherlands. Most of these studies have been repeat business, demonstrating the satisfaction of our clients.

PRA has an excellent track record enrolling large groups of subjects and meeting timelines for TQT studies. As an example, in 2014, we performed a multiple-dose, parallel, TQT study with 189 subjects. The first subject was enrolled in May 2014 and the last in July. Subjects were dosed in groups of up to 50.

The typical dropout rate in these studies has been 2-3% of the randomized subjects. To reduce the number of subjects needed in multiple-dose TQT studies, we perform studies with a “nested design,” which interweaves the moxifloxacin comparator group with the placebo group.

E X P E R I E N C E W I T H T Q T S T U D I E S AT P R A

Figure 2: Telemetry at PRA Clinical Pharmacology Units

Figure 1: Mortara ELI250 Cardiograph at PRA Clinical Pharmacology Units

Figure 3: Mortara 12-Lead X12+ Telemetry as Used in TQT Studies at PRA for

ECG Assessment During TQT & Early Clinical Development



The quality of TQT studies performed by PRA is illustrated by:

• Specific, documented training of PRA staff for Holter and single ECG recordings during the study.

• Repeat business for most TQT studies performed over the last few years.

• Written responses received from senior staff members of several core ECG vendors, which include: “excellent data quality, meeting all prior assumptions for adequate power” and “very high quality tracings collected for analysis were outstanding.”

In addition, PRA has never performed a TQT study that was inconclusive or had a failed moxifloxacin arm. As an example, in a study with 11,778 ECG extractions, only 45 extractions could not be analyzed due to artifacts.

E VA L U AT I N G E C G S D U R I N G E A R LY C L I N I C A L S T U D I E S

PRA performs numerous first-in-human studies. During the last 5 years, our CPUs in the US and The Netherlands performed 195 single- and/or multiple-ascending dose (SAD-MAD) studies.

Evaluation of ECGs during these early clinical studies typically involves the assessment of clinically significant, abnormal ECGs only. If statistical analysis is performed, traditionally it has been limited to descriptive statistics of ECG parameters.

Combined with Concentration Effect Modelling (CEM), precise estimates of QTc effect may substantially improve the ability to detect QTc prolongation early in the development process. The value of CEM for QTc evaluation in early clinical studies has been demonstrated by a study performed by the Cardiac Safety Research Consortium. The results of this study, presented during a meeting on 12 December 2014 at the FDA’s White Oak campus, support the concept that with careful assessment of ECGs, SAD and MAD studies may provide sufficient power to exclude a QTc increase at the level of regulatory concern. Whether or not the ECG results from early clinical studies can replace a TQT study will depend on the totality of the data.

PRA promotes a solid evaluation of ECGs during early clinical studies. The study may include:

• Triplicate ECGs

• CEM

• Storage of ECGs in FDA-compliant XML format



• Specific working instructions to reduce variability

• A rigorous ECG assessment similar to the study performed by the Cardiac Safety Research Consortium (IQ-CSRC, 2014) 2

To ensure we deliver quality, innovative study designs, PRA’s highly trained clinical pharmacology professionals collaborate closely with leading ECG core labs.

Biologics

For both small and large molecules, a rigorous assessment of the ECG during early clinical studies can turn out to be an excellent long-term investment.

Assessing effects of your drug on ECG parameters requires experience and the right study design, study assessments, and data analysis methods.

For any TQT study or an early clinical study, PRA offers the right experience and expertise in study design and execution. We have the procedures in place to deliver high-quality ECG data.

C O N C L U S I O N

The ICH-E14 guidance document was written with an emphasis on small molecule drugs and does not specially address QT assessment for biologics (Rodriguez, 2010)3. For large biologics, there is no clear requirement for a TQT study, but some degree of ECG assessment is expected (ICH, 2014)4. If large biologics do not have primary or secondary effects on cardiac function, they will likely not alter the QT or have a risk of TdP (torsades de pointes). Therefore, a database of high-quality ECG data from early clinical studies coupled with a clean cardiac profile from preclinical work is likely to provide adequate confirmation of cardiac safety for a large biologic, and may thereby allow a waiver for a dedicated TQT study (Rodriguez 2010).

R E F E R E N C E S

1 Darpo B, Fossa AA, Couderc JP, Zhou M, Schreyer A, Ticktin M, Zapesochny A. Improving the Precision of QT measurements. Cardiol J. 2011;18(4):401-10.

2 IQ-CSRC. Can QT Assessment in Early Clinical Development be used to replace the TQT Study – Presenting Results from the Prospective IQ-CSRC Clinical Study. White Oak Facility, FDA Headquarters, Silver Spring, Maryland, December, 12 2014.


© P R A H E A L T H S C I E N C E S . 10.15 5

For further information or to discuss any aspect of PRA’s services offered in the field of ECG assessments, please contact your Business Development Manager or the employee listed below:

Thijs van Iersel, MDSenior Director, Global Scientific AffairsPRA Early Development ServicesVan Swietenlaan 69728 NZ Groningen, The NetherlandsPhone: +31 (50) 402 2204Mobile: +31 (6) 517 614 [email protected]

World Headquarters4130 ParkLake Avenue, Suite 400Raleigh, North Carolina 27612 USAPhone: +1 (919) 786 8200Fax: +1 (919) 786 8201www.prahs.com

C O N TA C T I N F O R M AT I O N

3 Rodriguez I, Erdman A, Padhi D, Garnett CE, Zhao H, Targum SL, Balakrishnan S,Str-nadova C, Viner N, Geiger MJ, Newton-Cheh C, Litwin J, Pugsley MK, Sager PT, Krucoff MW, Finkle JK. Electrocardiographic assessment for therapeutic proteins--scientific discussion. Am Heart J. 2010 Oct;160(4):627-34.

4 ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Questions & Answers (R2), 21 March 2014.

A B O U T P R A H E A L T H S C I E N C E S

PRA Health Sciences delivers innovative drug development solutions that improve

patients’ lives. Our people are passionate about clinical research, working tirelessly

to provide quality results for clients. We offer exceptional experience across

all phases, therapeutic areas, and a broad spectrum of solutions, ranging

from full-service clinical development to our pioneering Embedded model.

With 12,000+ employees covering 80+ countries, we bolster an impressive

global presence with keen local insights. Our project teams harness their

understanding of local regulations, standards of care, and cultural customs

to effectively align our approaches with each study’s unique goals.

At PRA, we love what we do because we are making a difference in the lives of patients

and their family members worldwide. Over the years, we have contributed to the

development of numerous drugs now available to countless patients. From our scientific

and medical experts to therapeutically aligned project managers and monitors,

we provide the commitment and expertise needed for today’s complex studies.

To learn more about PRA, please visit www.prahs.com or

email us at [email protected].

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ecg assessment during tqt and early clinical studies

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