Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Abstract

After multiple drugs were removed from the market secondary to drug-induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical-industry perspective making the case that "double-negative" nonclinical data (negative in vitro hERG and in vivo heart-rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double-negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double-negative nonclinical data could be used to reduce the number of "Thorough QT" (TQT) studies and reach a low-risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a "stage 2" of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc-prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double-negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.

Figure 1

Types of clinical QT study report submitted to the FDA from 2016 to 2020: 44% were conventional thorough QT (TQT) studies, 32% relied on concentration‐QTc analysis as described in ICH E14 Q&A 5.1 (typically from phase I clinical trials), and 24% utilized alternative study designs described in E14 Q&A 6.1 (typically without placebo, positive control, and/or reaching exposure levels required for TQT or E14 Q&A 5.1). For study reports under E14 Q&A 5.1, only 42% reached 2 times high clinical exposure level, which has been the requirement under E14 Q&A 5.1 for waiving the need for positive control in a TQT study. Under the revised draft Q&A 5.1, with double‐negative nonclinical data the exposure will only need to reach high clinical exposure to waive the need for a positive control, allowing for more TQT substitutes. For study reports with alternative study designs (E14 Q&A 6.1), 82% were for oncology indications. Under the existing Q&A 6.1, studies can only reach a conclusion of “no large QTc effects.” Under the revised draft Q&A 6.1, when combined with double‐negative nonclinical findings, a conclusion of low likelihood of proarrhythmic effects due to delayed repolarization can be reached. FDA, US Food and Drug Administration; Q&A, question and answer.

Figure 2

Schematic diagram of how the new ICH E14/S7B draft Q&As fit into the original S7B Guideline. (a) Diagram from the original S7B Guideline. (b) New S7B Q&As on best practice considerations for the core S7B assays (hERG and in vivo QTc) and additional ion channel assays that may be used as follow‐up studies. (c) New S7B Q&As on best practice considerations for in vitro cardiomyocyte assays and principles for proarrhythmia models. (d) The new S7B integrated risk assessment Q&As in combination with the revised E14 Q&As describe how nonclinical data can be used to reduce the number of thorough QT (TQT) studies and reach a low‐risk determination when a TQT or equivalent cannot be performed. The integrated risk assessment also describes how follow‐up studies can be used to understand and predict TdP risk of QTc‐prolonging drugs, however, these are evaluated on a case‐by‐case basis. ECG, electrocardiogram; ICH, International Council for Harmonisation; Q&A, question and answer; QTc, heart rate corrected QT interval; TdP, torsade de pointes.

Figure 3

Illustration of how changes in the sensitivity and specificity of an assay on its own (e.g. hERG or in vivo QTc alone), or when used in combination with a second assay (e.g. hERG and in vivo QTc together), affect the post‐test probability of an outcome (e.g. clinical QTc or TdP risk). (a) Different sensitivity and specificity combinations for an assay to have moderate (negative likelihood ratio (LR−) = 0.3, dashed line) or high (LR− = 0.1, solid line) discriminatory power when the assay result is negative. As an example, an assay with  77% sensitivity and  77% specificity (dot on dashed line) has moderate discriminatory power (LR− = 0.3), whereas an assay with  91% sensitivity and  88% specificity (dot on solid line) has high discriminatory power (LR− = 0.1). (b) Relationship between pre‐test and post‐test probability after a single negative test. When the pre‐test probability is 10% (as used for TdP by Vargas et al.), a single negative test with moderate discriminatory power (LR− = 0.3, dotted line) results in a post‐test probability of 3.2%, while a single negative test with high discriminatory power (LR− = 0.1, solid line) results in a post‐test probability of 1.1% (horizontal dotted line). (c, d) Relationship between pre‐test and post‐test probability for a double‐negative drug. Note that a double‐negative result where both assays have moderate discriminatory power (LR− = 0.3, solid line in c) can bring a pre‐test probability of 10% to a post‐test probability of  0.99%. When one assay has high discriminatory power (LR− = 0.1), the post‐test probability decreases to 0.33% and when both assays have high discriminatory power the post‐test probability decreases to 0.11%. As a sensitivity analysis, d also shows how even when the pre‐test probability is increased to 30%, having one test with moderate and one with high discriminatory power (dot on dashed line) results in a 1.3% post‐test probability, whereas having high discriminatory power with both tests (dot on solid line) results in a post‐test probability of 0.43%.

Figure 4

The FDA cardiac safety interdisciplinary review team conclusions from clinical QT study reports submitted from 2016 to 2020: 19% were positive for QTc prolongation (i.e., upper bound above 10 ms), 24% were found to have no large QTc effects (i.e., unlikely to have an actual mean QTc effect of 20 ms or larger, primarily drugs under E14 Q&A 6.1 – see Figure 1 legend and text) and 57% were found to have no QTc prolongation (i.e., negative TQT study or equivalent under Q&A 5.1). QTc prolongation was observed in 20% of TQT studies, 10% of E14 Q&A 5.1 studies, and 19% of E14 Q&A 6.1 studies. Considering all study report types together, of the 19% of drugs that prolonged QTc, 33% were for oncology indications, 30% were drugs targeting the central nervous system (i.e., neurology, psychiatry, and anesthesiology/addiction/pain), and 37% were from all other therapeutic indications. These statistics do not capture drugs that underwent clinical QTc evaluation but were discontinued from development prior to the sponsor submitted a clinical QT study report. ECG, electrocardiogram; FDA, US Food and Drug Administration; QTc, heart‐rate corrected QT; TdP, torsade de pointes.

Figure 5

Proposed stage 2 topic for updating ICH E14/S7B on how to define low‐risk drugs that would not need detailed QT‐focused clinical evaluation

Figure 6

Proposed stage 2 topic for updating ICH E14/S7B ‐‐ how an integrated risk assessment including proarrhythmia models and ECG biomarkers can be used to impact clinical and regulatory decision making for QTc‐prolonging drugs. (a) hERG block alone (or predominant hERG block) causes QTc prolongation that can lead to TdP. (b) Balanced multichannel block (hERG block with concomitant inhibition of late sodium or L‐type calcium currents) can cause QTc prolongation that does not always lead to TdP. (c) Different types of indirect QTc prolongation (i.e., not mediated by directly affecting ion channels) may or may not be associated with TdP. (d) Evaluation of TdP risk through an integrated nonclinical‐clinical risk assessment. ECG, electrocardiogram; ICH, International Council for Harmonisation; Q&A, question and answer; QTc, heart‐rate corrected QT; TdP, torsade de pointes.