Georg Ferber

Can Bias Evaluation Provide Protection Against False‐Negative Results in QT Studies Without a Positive Control Using Exposure‐Response Analysis?

The revised ICH E14 document allows the use of exposure‐response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when this cannot be achieved, there may be a need for metrics to protect against false‐negative results. The objectives of this study were to create bias in electrocardiogram laboratory QT‐interval measurements and define a metric that can be used to detect bias severe enough to cause false‐negative results using exposure‐response analysis. Data from the IQ‐CSRC study, which evaluated the QT effect of 5 QT‐prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying electrocardiogram algorithm (COMPAS). The slope estimate of the Bland‐Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately −20 milliseconds over a QTcF range of 100 milliseconds to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. With the random methods, the rate of false‐negatives was ≤5% with bias severity < –10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false‐negative predictions with exposure‐response analysis.

Scientific white paper on concentration-QTc modeling

The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.

QT/QTc Prolongation in Placebo-Treated Subjects: a PhRMA Collaborative Data Analysis

In an ongoing effort to try to understand the variability of QT/QTc data and determine how that variability would affect the design, analysis, and conclusions drawn from data collected in thorough QT/QTc studies, five Pharmaceutical Research and Manufacturers Association (PhRMA) companies recently performed retrospective analyses of placebo and nondrug 12-lead resting electrocardiogram (ECG) data. The data were obtained from five rigorously conducted studies in which the collection and analysis of QT/QTc intervals was a primary objective. Variables that are known to affect variability of QT/QTc intervals, such as adequate resting time before recording the ECGs, food, and consistency of lead placement, had been well controlled in each of the studies. Single ECGs were recorded at each time point, and the QT intervals were measured by ECG laboratories.

Cardiac Safety of Rupatadine in a Single‐Ascending‐Dose and Multiple‐Ascending‐Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments—Comparison With the Previous White Caucasian Thorough QT Study

A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double‐blind, placebo‐controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days −1, 1, and 5 at several points, and time‐matched pharmacokinetic samples were also collected. Concentration–effect analysis based on the change in the QT interval corrected using Fridericias formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects.

Estimation of the Power of the Food Effect on QTc to Show Assay Sensitivity

The most recent International Conference on Harmonisation E14 Q&A document states that a separate positive control would not be necessary provided sufficiently high exposures are achieved in the early‐phase studies. Realistically, a phase 1 study is unlikely to include a pharmacological positive control, and in cases in which plasma levels of the drug exceeding therapeutic levels are not achieved, the lack of a positive control can constitute a limitation when excluding an effect of regulatory concern. It has been proposed to use the effect of a standardized meal on the estimate of the diurnal time course of QTc to show assay sensitivity. We conducted simulations by subsampling subjects from a 3 different studies and could show that the effect on food on QTc can be reliably prove assay sensitivity for sample sizes as low as 3 × 6 subjects with a power greater than 80%.

Evaluating Potential QT Effects of JNJ‐54861911, a BACE Inhibitor in Single‐ and Multiple‐Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration‐QTc Analysis

Nonclinical assays with JNJ‐54861911, a β‐secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4‐way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ‐54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high‐precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first‐in‐human single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo‐corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9‐18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure–response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ‐54861911 peak plasma concentrations (Cmax) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax, 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ‐54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.

Confirmation of the Cardiac Safety of PGF2α Receptor Antagonist OBE022 in a First‐in‐Human Study in Healthy Subjects, Using Intensive ECG Assessments

OBE022, a new orally active prostaglandin F2α receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first‐in‐human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration–effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration–response analysis showed the absence of QTc prolongation at all doses tested. Two‐sided 90% confidence intervals of the geometric mean Cmax for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug‐induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4‐way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day –1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24‐hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration‐effect modeling approaches, which presume the absence of hysteresis effects.

Study Design Parameters Affecting Exposure Response Analysis of QT Data: Results From Simulation Studies

The operating characteristics of dose‐escalating studies in terms of false‐negative predictions of the QT effect and the power to exclude clinically relevant QT effects are not quantitatively established. One thousand single‐ascending‐dose (SAD) studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with (1) 8 different QT effects of the study drug and (2) achieved plasma concentration 2‐ or 4‐fold above therapeutic levels. For each subject, drug‐free QT data from a thorough QT study were subsampled to capture the circadian profile, on which a drug effect was added. The percentage of false‐negative studies was between 4% and 9% when the drugs QT effect was set to 10 milliseconds. If a somewhat lower effect of 6.7 milliseconds was set at therapeutic concentrations, the fraction of negative studies was higher, 40% to 60% when the variability of the QT data was well controlled. When the QT effect was set to 5 milliseconds at therapeutic plasma concentrations, the power of SAD studies to exclude 10 milliseconds QT effect was generally above 70% (74% to 94%) with well‐controlled QT variability, whereas the power was reduced to 36% to 69% if supratherapeutic plasma concentrations were not achieved. The rate of false‐negative studies was acceptably low in placebo‐controlled SAD studies. With a drug with no or a small QT effect, supratherapeutic plasma concentrations, and well‐controlled variability of QT data, the power of SAD studies to exclude a relevant effect was above 70%.

Correction to: Scientific white paper on concentration-QTc modeling

The original version of this article unfortunately contained an error in Equationxa01 under the section “Pre-specified linear mixed effects model”. The correct equation has given below.