Cardiac Safety Assessments in Early Phase SAD/MAD Studies: An Intelligent Approach by Richmond Pharmacology

LONDON, December 11, 2014 /PRNewswire/ --

Recent proposals by the FDA to revise the ICH E14 guideline include the suggestion that the requirement for a thorough QTc study (TQT) may be waived and or replaced by data generated during First time in Human (FTIH) single ascending dose (SAD) and multiple ascending dose (MAD) studies. This will be one of the topics of an imminent CSRC meeting in Washington. Peer reviewed publications suggest that small studies are capable of showing an effect where there is one; the challenge is to prove no effect. This is why typically a medicine with a known QTc prolonging effect is given to confirm the (assay) sensitivity of each study.

SAD and MAD studies do not typically include a pharmacological control to confirm ECG assay sensitivity. This is a major limitation when using their data to exclude an effect as systematic errors may have occurred limiting the sensitivity of a study thereby giving a false negative result. Unlike random error, which will lead to very wide confidence intervals thereby not allowing to exclude a 10ms change in QTc, systematic errors cannot be reliably detected other than by including a positive control. The use of a positive control sample is a generally well-accepted principle in biologic research.

We have previously demonstrated^[1] that the analysis of ECG obtained one to four hours after the intake of a meal offers the opportunity to demonstrate the physiological QTc-shortening which normally occurs after every meal; this is correlated to the release of c-peptide into the circulation. This effect is sufficiently small that -- if established -- it gives confidence that a study had adequate sensitivity to show an effect on QTc if there had been one. The method is well publicised, highly reproducible and robust even in small populations and has been consistent across published work^[1,2]. The main factors that allow the analysis of food effects on QTc are as follows:  (1) two to three ECG samples are taken during 1.5-4 hours following a meal; (2) the meal should be rich in carbohydrates in order to provoke c-peptide release; (3) the research participants should not be c-peptide deficient, i.e. type 1 diabetic; and (4) in cases where more than one meal is given, subjects should be fasting for at least 4 hours before the meal that is used for analysis; this is in order to avoid collecting a false negative (still shortened after a previous meal) QTc baseline. This last recommendation is in response to a recent paper (2014) by Hnatkova et al. entitled "QTc Changes after Meal Intake: Sex Differences and Correlates" published in the Journal of Electrocardiology^[3], in response to which  we have issued a letter to the editor^[4] to address apparently confounding results of QTc prolongation reported by the authors. View open access article.

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References

1. Taubel J, Lorch U, Ferber G, Singh J, Batchvarov VN, Savelieva I, Camm AJ. Insulin at normal physiological levels does not prolong QTc interval in thorough QT studies performed in healthy volunteers. Brit J Clin Pharmacol. 2012; 75: 392-403.
2. Taubel J, Wong AH, Naseem A et al. Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol 2012; 52: 1558-1565.
3. Hnatkova K, Kowalski D, Keirns JJ, Van Gelderen EM, Malik M. QTc Changes after Meal Intake: Sex Differences and Correlates. J Electrocardiol. 2014. [Epub ahead of print] DOI:http://dx.doi.org/10.1016/j.jelectrocard.2014.07.026
4. Taubel Jorg, Ferber Georg, The reproducibility of QTc changes after meal intake, Journal of Electrocardiology (2014), doi: 10.1016/j.jelectrocard.2014.11.006
   

SOURCE Richmond Pharmacology Limited