A set of data standards and data quality criteria will be available to allow sponsors to assess the suitability for their data prior to submission to the FDA.
The “regulatory” model used in decision making will be available online but will be limited its ability to incorporate experimental data on drug-channel kinetics. However, sponsors will be able to run simulations using IC50 values to explore possible simulated responses.
Not necessarily. As new data emerge and it is determined that the predictive performance of the model can be improved, the model will be updated. If this occurs, it will be necessary to review how the changes impact prior predictions of relative risk and any regulatory decisions made on those results.
As these tests may be done during the discovery phase and prior to knowledge about effective clinical drug levels, a range of concentrations will be evaluated to unmask behaviors associated mechanistically with the clinical risk of TdP.
The current strategy is to keep the process as simple as possible and generate manual voltage clamp data only for the hERG channel, looking at potency and kinetics of block. Manual experiments are performed using the same protocol at both room and physiologic temperature to address its potential effect on potency.
The following channels will be studied:
• Recombinant Human channels expressed in replicating cell lines
• IKr = hERG
• Ica (L-type) = Cav1.2
• INa = Nav1.5 peak and late current – drug modified late Nav1.5
• ITO =Kv4.3
• IKs = KCNQ1+KCNE1
• IK1 = Kir2.1
It is likely that this list of 7 targeted channels will narrow once their role as proarrhythmic markers are confirmed, or refuted, based on experimental outcomes
Following a February 2016 CiPA Steering Committee meeting, it was agreed that all non-hERG channel data would be generated using high throughput automated voltage clamp systems (HTS). Consequently, a new HESI-sponsored Work Stream was formed to 1) assess the transfer of the hERG protocols from manual to HT systems; 2) to assess the variability and reproducibility of HT platforms/sites for defining drug effects on cardiac ionic currents, and 3) to provide IC50 data for all non-hERG channel to the in silico group for model validation.
The impact of this variable will be addressed by the HT evaluation work. However, from a practical point of view this would be technically challenging, and may not be necessary.
The ongoing HT evaluation will include the following platforms: QPatch, Synchropatch, CytoPatch, IonWorks and IonFlux.
Validation studies will be performed at physiologic and room temperature on systems that have the ability to regulate temperature. Otherwise, experiments will be performed at room temp, or more realistically, individual HT platform temperature.
Calibration standards performed each for each experiment will define assay sensitivity and place results from different preparations (and platforms) in context.
There is no set order in which the CiPA assays need be performed. It may be possible to employ myocyte studies early in drug discovery. Further studies are needed to define overall assay sensitivity.
In vitro concentrations will be compared across anticipated therapeutic and supratherapeutic exposures. While a direct correlation based on in vitro and in vivo concentrations may not always be possible, the position and steepness of the concentration-response curves will be considered as part of the overall risk assessment. The extent of plasma protein binding should also be considered during these relatively acute experiments. As different technology platforms may perform best in the presence or absence of plasma proteins, such conditions will be noted and considered in regards to nominal free drug concentrations.
Experiments will be performed at 35-37oC. Recordings from spontaneously active or paced preparations will be considered (with data provided with and without correction factors for beating frequency).
Discrepancies between responses recorded from stem cell myocytes and in silico reconstructions will need to be discussed. Responses of novel therapeutics would also be compared to clinical drug standards ranked according to the CiPA proarrhythmia categories (low/no risk, intermediate risk, and high risk) and evolving Phase 1 ECG biomarkers to provide further context for results. In the future, comparisons with in silico reconstructions of stem cell myocyte electrical activity may provide further mechanistic insights into the integrated, cellular responses recorded.
To use human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data.
No, the primary prediction of proarrhythmic risk will come from the in silico model. The ECG assessment will provide confirmation that there are no unexpected ion channel effects in humans.
New ECG biomarker(s) would need to add additional information beyond PR/QRS/QTc:
- Differentiate multi-ion channel effects during repolarization
- Can be corrected for heart rate (if needed)
- Sufficient power to detect changes in small sample sizes with exposure-response analysis
- Available for wide-spread use
A new prospective clinical trial with small sample size and similar in design to first in human single/multiple ascending doses is being planned for completion in 2017. It is anticipated that 6 additional drugs will be studied. Additional analysis is also being performed on prior Thorough QT studies with comparison to multi-ion channel assessment in voltage clamp studies.