Robert G. Hunter BCC Research

Continuing to provide a powerful example of effective collaboration.

In response to adverse events about a decade ago, the field of drug cardiac safety testing came together and mandated an integrated testing strategy, which helped spawn a vibrant landscape of in vitro screening tools linked to refined in vivo methods. And now in the face of recent technical and clinical progress, the strategy is being voluntarily updated and a new in silico drug development model added. Facilitated by HESI (the Health and Environmental Sciences Institute;, this illustrates how effective global cross-sector collaboration can lead to clear guidelines and hence to strong innovation and commercialization.

Faced with serious cardiac arrhythmias (Torsades des Pointes, also known as Long QT Syndrome), the cardiac safety field recognized that guidelines were urgently needed.  HESI undertook a program to evaluate the utility of preclinical safety testing assays for predicting clinical TdP. The published results of these studies served as supporting experimental data for the subsequent development of the ICH S7B guideline, now fully adopted in Europe, North America, and Japan. Since the implementation of this guideline, the occurrence of unanticipated TdP effects from approved drugs has been largely eliminated.

Yet in an impressive display of continuous process improvement, global leaders have recently acknowledged that the current ICH S7B (nonclinical) and E14 (clinical) guidelines “have had the unintended consequences of propagating an inaccurate understanding of the safety risk associated with the (surrogate) signals. The perception that detection of even a small effect…will result in adverse regulatory and commercial implications during drug development has significantly impacted the pharma discovery pipeline, as up to 60% of new molecular entities are testing positive and are thus being abandoned early in development.” 

Furthermore, evolution in technical, clinical, and regulatory understanding over the past several years has revealed a broader array of risks and signals that need to be considered. The week of March 10, 2013, marked a major milestone in efforts between ICH, FDA, MHRA, and other drug regulatory agencies, as well as key industry and academic leaders and scientific consortia worldwide, to forge a new approach. 

The new paradigm returns to the core objectives, pointing out that the existing strategy does not directly assess the end point of primary clinical concern, namely ventricular TdP. Rather, it provides a regulatory framework for the detection of delayed ventricular repolarization as represented by two surrogate markers:

  1. Preclinical in vitro and in vivo assays to detect “hERG current block,” or block of the repolarizing potassium ionic current IKr that flows through the ion channel encoded by the gene hERG; and
  2. Clinical focus on QTc prolongation (the QT interval “corrected” for the effects of heart rate), which has been considered as an initiating factor in clinical TdP. 

Since its adoption, it is now appreciated that the effects of hERG current block may be modulated by multiple cardiac ion currents during repolarization, and that hERG current block sometimes does not provide a meaningful indicator of proarrhythmic risk. In fact, while focus has centered on hERG among a dozen or so ion channels (across cardiomyocyte membranes) known to be involved in maintaining the cardiac action potential, it is estimated that there are more than 70 types of ion channels that are differentially expressed across the repertoire of cardiomyocytes. 

The new strategy proposes multiple ionic current measurements using cardiomyocytes in a Comprehensive In Vitro Proarrhythmia Assay (CiPA), along with careful Phase I ECG assessment, to enhance mechanistic detection and interpretation of proarrhythmic potential.  (Note that considerable efforts have also been invested to address nonarrhythmic risk factors as well, integrating a range of structural and functional end points.)

Stem cell technology has matured significantly and some see a future in which clinical applications could be targeted for specific subpopulations, even individuals.  And yet their sensitivity, specificity, and reproducibility remain the subject of much current evaluation. 

In Silico: Model-Based Drug Development and Mechanistic/Predictive Combos

It is becoming standard practice in drug development for pharmaceutical companies and FDA to estimate clinical trial doses using computer models to evaluate why adverse events occur, and to determine the potential basis for variable patient response. In June 2013 the FDA issued a regulatory letter to Critical Path Institute’s consortium the Coalition Against Major Diseases (CAMD), deeming CAMD’s quantitative clinical trial simulation tool a “fit-for-purpose” drug development tool for Alzheimer’s disease. And in September 2013, FDA announced a licensing agreement for use of PhysioLab Modeler software to study drug-induced liver injury.

In drug cardiac safety over the past decade the pendulum swung pretty far to the mechanistic side. And now FDA is playing a formative role by bringing this new cardiac in silico model to provide complementary predictive strength. 

Powerful Combination

Initial collaboration has led to dramatic results in drug cardiac safety testing over just the past decade. And now this new effort underscores the value of this example for other areas of predictive safety and toxicology. 

According to HESI executive director Syril Pettit, notable aspects of this success include the breadth of the collaboration, from safety pharmacology, biotechnology, computer modeling, cellular physiology, to clinical medicine. Another key was the scope of the global collaboration. Says Pettit, “We firmly believed that for this new paradigm to be adopted and gain traction it will be important to get all global players aligned. We seek to avoid a scenario where two distinct testing paradigms co-exist as that would create uncertainties in interpretation and inefficiencies in resource use.” Efforts to engage diverse partners and communities of practice have also led to involvement of other expert groups such as the Safety Pharmacology Society and Cardiac Safety Research Consortium.

She went on to emphasize that this “science without borders” philosophy is inherent in HESI’s approach to precompetitive consortiums. Judging from their earlier success leading to ICH S7a/b (which was actually the first ICH guideline to use safety pharmacology data from a nonclinical safety setting to inform potential clinical risk) and now this important update, it seems to be working! 

Robert G. Hunter ([email protected]) is the author of “In Vitro Toxicity Testing: Technologies and Global Markets,” published in December 2013 by BCC Research. For more information see

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