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International Clinical Trials

Heart of the Matter

In December 2014, the news of a technique for assessing QT/QTc from data captured during Phase 1 clinical trials was shared during the FDA-hosted Cardiac Safety Research Consortium (CSRC) meeting. This new concept is an adaptation from the original model for assessment of potential drug-induced proarrhythmia, currently evaluated under the FDA's Thorough QT (TQT) guidance issued in 2005 (1). Over the last decade, QTc studies have been conducted at a cost of about $2-4 million per study for almost all new chemical entities (NCEs) exhibiting systemic exposure.

TQT represents a significant investment risk, given that a positive finding can result in onerous late-stage or post- approval commitments for safety monitoring; encumber a product with warning labels; and ultimately completely end the development of a compound, if the burden is considered to outweigh the potential risk or market value of the drug as determined by the pharmaceutical company involved.

The FDA's 2005 guidance has met its objective, to identify drugs that could potentially cause torsades de pointes – a dangerous cardiac arrhythmia that can result in sudden death. While admirable, the question within the industry has been how many potentially viable drugs have been shelved or discontinued due to possibly false QT signals in either non-clinical or clinical R&D?

Early Assessment

As reported in The Wall Street Journal on 17 December 2014, a study was recently completed “in collaboration with the FDA which demonstrated that cardiac toxicity in drugs can be detected much earlier in the development process than previously thought by medical professionals" (2).

The CSRC-FDA project, entitled 'The IQ-CSRC Prospective Clinical Phase I Study: Can early QT assessment using exposure response analysis replace the Thorough QT study?', showed that new cardiac technology allows QT assessment to be conducted as early as during a first-in-human (FIH) dosing trial (3). These studies are typically administered to healthy normal volunteers in single doses to small cohorts in an ascending manner, with the objectives of evaluating safety, tolerability, pharmacokinetics and potential dosing regimen for further trials in patient populations.

Newer and more rigorous modelling techniques are being used to maximise the power of smaller-sized studies with increased data collection and analysis. The methodology features a considerable increase in electrocardiogram (ECG) data evaluation, use of improved automated algorithms for cardiac assessment and careful analysis of compound systemic exposure, to create a powerful combination of maximal data-points in a smaller clinical trial that is performed as part of a required FIH study.

Current TQT Methodology

The present requirement is for most NCEs to have a completed TQT study as part of the new drug application to the FDA for final approval. As it is an expensive proposition, a TQT study is often delayed until proof-of-concept (POC) in patients is demonstrated, and the therapeutic dose range and regimen have been defined (most often in Phase 2). It is often conducted in parallel with Phase 3 pivotal testing.

In line with the 2005 FDA guidance, the current design is a standalone study and measures the QT effect over a time course correlated to pharmacokinetics, which have been defined by this point. The general study design can be either a parallel or crossover one that includes drug at therapeutic and supratherapeutic dose – a dose significantly high enough to address potential toxicity in cases of drug-to-drug interaction or renal/hepatic impaired patients where the drug may not be cleared from the system as expected, resulting in higher systemic exposure levels. It also has a placebo and positive control arm where subjects are administered a dose of moxifloxacin. The objective is to indicate capability of detecting a 10 millisecond prolongation of the QT interval.

To further complicate matters, there has been a marked incidence of studies – upward of 12% – that have not showed positive QT in the moxifloxacin arm, leading to inconclusive study results (4). Again, the failure of a compound to exclude the QT effect has major consequences, notably project devaluation or discontinuation, marketing disadvantages associated with labelling constraints, and potential delays in FDA approval.

Adapting to Demand

The change of paradigm reflects the growing trend of early development studies to have parameters included in addition to safety and tolerability. As drug programmes expand in scope and expense, pharma companies are raising the bar on which ones to proceed into Phase 2 by expecting some hint of efficacy or other value-added data in the first studies.

Early QT assessment of drug candidates offers additional value to a variety of stakeholders. The data gathered in the FIH, single ascending dose (SAD) or multiple ascending dose (MAD) environment is the first opportunity to confirm preclinical cardiovascular safety findings, conducted either in vitroor in non-human models. Drugs that have tested positive in non-conclusive preclinical screening methods (Purkinje Fiber, ion channel and hERG assays) can potentially be 'saved'.

For organisations fortunate enough to have several drug candidates to evaluate for a particular development programme, early QT assessment can de-risk those drugs by providing a more precise indicator of arrhythmia liability prior to late-stage investment. Furthermore, the improved early-stage development package information that is used for licensing or further in-house R&D provides value to those looking to partner the programme, especially if there are sufficient data supporting a potential TQT waiver.

High-Precision Analysis

High-precision QT analysis combined with concentration/ effect modelling has been demonstrated to overcome the traditional, limited semi-automated ECG reading approaches that cannot exclude minor QT effect and have insufficient power to overcome variability due to low precision (5). The high-precision method allows for TQT-like statistical power in smaller studies such as SAD and MAD trials.

Using Holter monitoring systems equipped with Bluetooth® technology, it is now feasible to extract up to ten heartbeats during a defined time-point, as opposed to three. When this new technology is coupled with advanced automated overreads that evaluate the quality of multiple waveforms, not simply the QT complex, statistically-powered datasets can be obtained from small cohorts of subjects. This requires significantly fewer subjects, when compared with traditional QT studies that generally call for four study arms with 40 subjects per arm (crossover study design used here as minimal subject number).

Potential Designs

Early QT assessment techniques are highly flexible and can be included in several study scenarios during Phase 1a/1b. Its broad applicability and approach of using a limited sample number means that organisations can use this assessment at multiple points during compound development. Ideally, this would be done as part of the FIH or early MAD studies to inform future programmes; however, there is ample opportunity to include it as a part of other designs.

SAD studies enable cardiac safety to be assessed at very high doses, which may not be administered again during development. It can be argued that the supratherapeutic dose could be covered in this.

Advantages of monitoring cardiac safety during a MAD study are also clear. For example, the repeated dose administration will allow coverage for potential metabolite accumulation, as well as address instances where steady-state metabolite formation is different in single administration versus multiple administrations, or where the QT prolongation occurs through a delayed mechanism, such as hysteresis.

Cardiovascular safety assessment can be made in studies that are directly administered for the first time in humans to patient populations. Most commonly, this occurs with drugs used in oncology patients. Under well-defined safety conditions, intense cardiac monitoring is included in small patient cohorts. Patients also directly receive NCEs in POC studies towards the end of FIH/SAD/MAD adaptive designs after safety and tolerability has been monitored in healthy normal volunteers. Often, the medical status of the healthy normal volunteers and the patients can yield important differences and inform sponsors of the cardiac safety in the patients. In addition, even though there is not a formal requirement for biologic drugs to evaluate QT potential, this early QT assessment may mean cardiovascular safety can be monitored at a reasonable expenditure during early drug development.

Logistics and Operations

Design of clinical pharmacology studies featuring an early QT assessment can be complex, whether they involve patients or only healthy normal volunteers. Many clinical pharmacology units (CPUs) have broad expertise in executing standard registry studies; however, the facility demands and logistical concerns of an early QT study can be more challenging, given the number of time-points that involve pharmacokinetic sampling, safety assessments, adverse-event monitoring and cardiac assessment.

The study volunteers’ environment can clearly contribute to quality of the data obtained. It is preferable that subjects be quietly sequestered in a relaxed atmosphere, as opposed to mixed into a larger group of subjects enrolled in different ongoing studies. Subjects with privacy and more recumbent resting time will have better resting heart rates and improved cardiac data. Timing of cardiac sampling should precede other data collection in the operational flow of the study – for example, blood sampling should occur after the cardiac monitoring to avoid rapid spikes in resting heart rate.

Facilities should be set up to handle the amount of electromagnetic interference and additional power requirements necessary for intensive ECG readings in order to avoid electronic background noises that can contribute to poor-quality data. Hospital-based units should mitigate the electronic interference effects of equipment, such as positron emission tomography or magnetic resonance imaging, by ensuring they are physically distant from the CPU.

Clear Pathway

The industry is set to adapt after a decade of experience with the TQT study with no current withdrawals based on QT prolongation. Newer ECG technology with higher precision and the inclusion of exposure-response analysis has made possible a new era for the industry where early development study designs include high-quality QT analysis. This methodology may alleviate the need for the traditional TQT approach.

Questions around the FDA's acceptance of this new paradigm was addressed frankly by Dr Norman Stockbridge, a Director in the Division of Cardiovascular and Renal Products at the FDA’s Center for Drug Evaluation and Research. He told The Wall Street Journal: “If a pharma company comes to me with results using this type of a methodology, and the study is well-conducted with high-quality ECG data collection and analysis, I am ready to recommend its use in regulatory decision-making today” (6).

Considerations now under discussion relating to the potential criteria for a negative QT assessment are focusing on the upper bounds of the two-sided 90% confidence interval of the predicted placebo-adjusted change in QTcF being <10ms at clinically relevant plasma levels of the drugs (5).

The clear pathway for early QT assessment is a revolutionary methodology. It frees pharma companies to evaluate their potential therapies earlier in the process, gives more product valuation for those looking for investment or partnering and, most importantly, creates an early translation of preclinical cardiac safety studies into viable human data and a safety platform for further development.

References
1. FDA Guidance for Industry: E14 Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Visit: www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformation/guidances/ucm073153.pdf

2. Or A, Norwest’s iCardiac seeks to be game-changer with new cardiac safety test, 16 December 2014. Visit: http://blogs.wsj.com/privateequity/2014/12/17/norwests-icardiac-seeks-to-be-gamechanger-with-new-cardiac-safety-test/?keywords=norwest
3. The IQ-CSRC Prospective Clinical Phase I Study: Can early QT assessment using exposure response analysis replace the Thorough QT Study?,Annals of Noninvasive Electrocardiology. Visit: http://onlinelibrary.wiley.com/doi/10.1111/anec.12128/pdf
4. Expert opinion: Development of cardiac safety translational tools for QT prolongation and torsade de points. Visit: http://informahealthcare. com/doi/abs/10.1517/17425255.2013.783819
5. Darpo B, Results from the IQ-CSRC prospective study: Can early ECG assessment replace the thorough QT Study?, presentation at the Cardiac Safety Symposium, 17 February 2015
6. Or A, Norwest-backed iCardiac to expand its market thanks to breakthrough, 16 December 2014. Visit: www.icardiac.com/portals/0/PDFs/norwest-backed%20icardiac%20to%20expand%20its%20 market.pdf

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Lorraine Rusch is Vice President, Business Development, at Vince & Associates Clinical Research. She is an executive-level business development professional and scientist specialising in early clinical development services, and provides a consultative service tailored to the needs of biotechnology and pharmaceutical clients. Lorraine earned her PhD in Laboratory Medicine and Bioanalytical Chemistry from the Cleveland Clinic Foundation/Cleveland State University Consortium.
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