Can early phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature
Article by SGS Clinical Pharmacology Unit Antwerp, Belgium; authors BERGHMANS PIETER-JAN, MD, SERLUPPENS NINA
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INTRODUCTION Thorough QT (TQT)-studies are recommended according to the 2005 ICH E14 guidelines to assess the potential of novel drugs to prolong QT interval. These stand-alone studies are expensive due to the large amount of subjects and typically carried out in Later Phase drug development. Replacing TQTstudies by incorporating QT-effect measurements in Early Phase SAD/MAD trials with an Exposure-Response (ER) QT-analysis could be an alternative enhancing cost-efficiency.
METHODOLOGY Literature study, 22 articles were selected for review.
Limitations of TQT The TQT-study has been successful in terms of detecting drugs with a QT effect and thereby avoiding the introduction of new drugs with an unknown QT liability to the market. However, TQT-studies are expensive and require a large number of subjects to be included. Furthermore, they are oversensitive and carry a certain risk for false positives due to a conservatively chosen threshold (10 ms) and the requirement that the QT-effect analyses is evaluated separately at each post-dosing timepoint for (supra) therapeutic concentrations.
Advantages of Early Phase ER-analysis The ER analysis uses all data of different subjects across a wide range of plasma concentrations of the drug and is enhancing the power to detect and exclude small QT-effects. This allows the ER-analysis to detect QT effects with the same power in a smaller amount of subjects, like Early Phase SAD/MAD designs.
Evidence Current literature provides promising evidence for this Early Phase ECG approach. Multiple trials, each investigating a different single compound per study, all managed to confirm the results of the TQT study by Early Phase ER-analysis.1,2,3,4
More supporting evidence can be found in the IQ-CSRC trial.5 Investigating 6 well known drugs, this trial managed to correctly categorize every single compound (5 QTprolonging/ 1 non QT-prolonging) using a Phase 1 setup and ER QT-analysis (Table 1).
Furthermore, the authors identified key characteristics to enhance statistical power (in a cost-efficient way) for the ERanalysis in a Phase 1 setup:
- Sample size: ≥ 9 subjects with supra therapeutic dose, ≥ 6 placebo subjects (Ferber et al, figure 1 + 2 )6
- Triplicate ECG in 5 min interval (Lester et al, Figure 3)7
- 6-8 ECG timepoints first 24h post-dose (Darpo et al)8
- Focus ECG timepoints around Tmax (Shah et al)9
Challenges to face Dubious results due to borderline ER-analysis might still result in the need for a TQT-study. Also the absence of a positive control arm (to confirm sensitivity) in Early Phase trial remains a point of discussion.
However, the confidence in a negative QT-assessment in the absence of a positive control will be higher when supratherapeutic drug levels are achieved (which is typically the case in Early Phase SAD/MAD).
CONCLUSION Literature provides growing evidence to perhaps partially replace TQT-studies with Early Phase ECG assessment. The data suggest that compounds with a clean pre-clinical profile and a robust negative Early Phase ER-analysis, can waive the request for a later phase TQT-study. A possible point of concern remains the lack of positive control arm in an Early Phase setup.
More research needs to be performed to further confirm the potential of ER-analysis in Early Phase setup. If the outcome of this investigation is positive, this should be seen as an opportunity to review the 2005 ICH E14 guidelines.
When applying early phase ER-analysis, the cost of the Phase 1 SAD/MAD design study will increase. However, when using data from SAD/MAD studies and obtaining the same statistical power as an extra and large TQT-trial, it is cost reducing in the overall development of a drug.
The cost/benefit ratio is definitely worth exploring and considering.