QT Studies for Biologics QT assessment in phase I Workshop 2

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1 QT Studies for Biologics QT assessment in phase I Workshop 2 Philippe L Hostis Joint Conference of European Human Pharmacological Societies and 20th Anniversary of AGAH Berlin, 31st March 2011

2 QT assessment in Phase I Context TQT studies are not always possible or requested, but data on potential QTc prolongation must be available Reliable QT data is helpful to conduct the further drug development Increasing need for a deep evaluation of the effect of the compound on the cardiac repolarisation and QT interval during early development studies

3 QT assessment in Phase I The advantages Subject profile is adapted: healthy young volunteers Potential cardiac safety issues are well covered by safety studies Good quality of ECG recording in CPUs In ascending dose trials, the dose range is wider compared to an E14 TQT study (therap & supra-therap dose)

4 QT assessment in Phase I The disadvantages The parallel group design is usually preferred (no cross over) The use of a positive control to assay sensitivity is not possible The ideal practical conditions for ECG recording can be difficult to achieve in CPU due to conflict with other safety assessments: early development trials are safety studies. The evaluation of the QT interval cannot be considered as the priority. The sample size is too small to provide sufficient statistical power

5 QT assessment in Phase I The sample size is directly related to the QTc variability (average standard deviation observed on the study population) Decrease of the QTc variability is the key factor for reliable QT assessment in early phase trials Strategies to reduce QTc variability Enhance the quality of the recording Increase the amount of analysable ECG: Use adapted QT/QTc measurement methods

6 QT assessment in Phase I Quality of recording Use of adapted devices Practical conditions Subject preparation Subject environment Subject condition during recording Review of the schedule of safety assessments: Identification of resting periods Introduction of QT specific procedures On line monitoring of the quality of recording Automatic assessment Alert

7 Quality on-line monitoring Technical quality index: Noise level: low and high frequencies Electrode position Heart rate stability Twave amplitude Calculated for each ECG recorded Associated with alert systems ( ) and quality metrics

8 Quality on-line monitoring Quality score monitoring Quality score (mean value) M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 Time (month) Site 1 Site 2 Site 3 Helpful for Core Lab & CPU to implement corrective actions, additional training sessions,

9 Reduction of QTc variability It is necessary to have more analysable data: More timepoints More replicates More drug free ECG (advanced QTc methods) Feasibility: The workload for ECG collection must not be directly related to the number of ECG The methods for ECG analysis must be highly automated

10 Reduction of QTc variability Number of replicates Impact of replicates number on QTc variability 10 QTc variability Number of replicates Biotrial TQT study internal database The optimal number of replicates is 3 (classical cost/benefit approach), but can be increased with an highly automated method for collection and analysis

11 The QTcI approach has a significant impact on the QTc variability Reduction of QTc variability QT correction method Impact of QT correction on variability QT QTcB QTcF QTcI Variability (ms) Biotrial TQT study internal database

12 Reduction of QTc variability QT/RR relationship Biotrial TQT study internal database High number of drug free ECGs Wide RR range QT hysteresis included in the modelisation

13 Continuous ECG recording Increased amount of available ECG data due to continuous 12-lead ECG recordings Devices are small, patient and user friendly System is cost effective, easy to set-up and maintain Limitations concerning access to safety ECGs

14 Continuous ECG recording ECG 12D 10 seconds ECG Safety review Double-clip Electrodes QT assessment Holter 12D Continuous recording + ECG extracted A possible implementation for safety ECG collection and continuous ECG recording

15 Continuous ECG recording Possible optimisation of the time of extraction based on : Noise level Heart rate stability RR variation RR (ms) Time

16 Continuous ECG recording Definition of the optimal time of extraction within a time window around theoretical timepoint ECG 1 ECG 2 ECG 3 time

17 Continuous ECG recording Implementation of a fully automated reading method: Automatic algorithms are reliable if: the ECGs are normal (T wave morphology) the recording is of good quality Cardiologist significant corrections of the automatic measurements only on a limited part of the ECG

18 Automated QT reading method Selection of ECGs where the QT automatic measurement is not reliable enough Score: 0 -> 100 Quality (noise, baseline drift, electrodes placement, ) Variability Out of range values Particular T wave pattern

19 Automated QT reading method Low Score (reliable QT measurement):

20 Automated QT reading method High score (unreliable QT measurement):

21 Automated QT reading method Score distribution - Phase I study (820 ECG, YHV): 50% 45% 40% 120% 100% Distribution 35% 30% 25% 20% 15% 80% 60% 40% Cummulative 10% 5% 20% 0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Quality score 0%

22 Automated QT reading method Score distribution - Phase I study: 25% 120% 20% 100% Distribution 15% 10% 80% 60% 40% Cummulative 5% 20% 0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Quality score 0% 804 ECG, Elderly HV, 2 sites

23 Automated QT reading method Decision for manual reading based on score threshold: 50 QT measurement (ms) Automatic values Cardiologist values 3.5% ECG reviewed by cardiologist

24 Automated QT reading method Decision for manual reading based on score threshold: 30 QT measurement (ms) Automatic values Cardiologist values 23% ECG reviewed by cardiologist

25 QT assessment in Phase I Conclusion 24-hour Continuous ECG recording (pre dose and post dose) High quality recordings Highly automated QT measurement with adapted QTc method Reasonable QT assessment Exploratory data, provide guidance for further drug development