Written by: Dr. Robert Kleiman, Chief Medical Officer & Vice President, Global Cardiology
The ICH E14 Implementation Working Group (IWG) released a third set of Q&A responses on March 21, 2014. The latest document discusses concentration response modelling of QTc data as well as three “special cases”. Overall this Q&A adds valuable commentary and guidance regarding some of the questions about Thorough QT Studies (TQTs) – though a variety of additional topics would still benefit from further clarification.
The first topic addressed by the new Q&A document concerns the use of concentration response relationship (CRR) modelling of TQT data. At the time that the ICH E14 guidance was drafted, CRR assessment was still considered an area of “active investigation”, but it has since become a very important and well respected part of the assessment for the proarrhythmic potential of new drugs. The new Q&A document explains that the CRR can be a useful part of a drug’s evaluation, and goes on to explain the importance of prospectively describing the pharmacokinetic-pharmacodynamic (PK-PD) models which will be used. This is to avoid post hoc attempts to utilize as many PK-PD models as possible until one finds the “best” PK-PD model which yields the most desirable results. The IWG also acknowledges that there are situations in which a QT effect is delayed or persistent when compared to plasma concentrations, resulting in an exposure response relationship that shows hysteresis. This may occur when a long acting metabolite has QT effects, when there is myocardial accumulation of a drug or metabolite, or when there are delayed effects on ion channel trafficking. The IWG briefly discusses the use of PK-PD models which incorporate hysteresis, and then discusses the situations in which analysis of CRR may be useful. This includes the estimation of the QT effect of doses of a drug which have not been formally tested, clarifying ambiguous QTc results from a TQT or early phase study, or helping to predict the QTc effect of factors which may alter a drug’s PK.
The IWG then proceeds to discuss 3 “special cases”. First, when a single dose crossover design TQT is not feasible, the IWG mentions that alternative designs using a parallel arm design, using patients with the targeted disease rather than healthy volunteers, or using other alternative designs may still be possible. When a placebo controlled arm is not appropriate (as is the case for many new oncologic agents), the IWG recommends that study designs should incorporate as many of the usual TQT features as possible. In particular, intense ECG and PK collection during early phase ascending dose studies, or even in a late stage trial, may be able to provide sufficient data to assess a drug’s proarrhythmic risk.
The IWG then briefly discusses QT assessment for combination drug products. If the component drugs in a new product have all undergone TQTs which show no relevant QT effects, then a TQT or intense late stage ECG monitoring will probably not be necessary. However, if one or more of the component drugs has never had a thorough QT/QTc assessment, the IWG states that they may be evaluated in combination or independently.
Finally, the IWG states that large targeted proteins and monoclonal antibodies have a low likelihood of direct interactions with ion channels, and therefore a TQT would usually not be required unless there are unusual circumstances suggesting the potential for proarrhythmia.
While this latest Q&A document does clarify some of the important issues which remain regarding the QT/QTc assessment of new drugs; further clarity would still be helpful regarding several other issues, including:
- Use of PK-PD models which better account for the effects of active metabolites
- The need for use of a positive control when a drug can only be studied in patients
- How best to assess combination products: the IWG statement about performing QTc evaluation of “independently or in combination” does not clearly help us understand the design elements which would best meet regulatory approval
- The best strategy for assessing the QT/QTc effects of large proteins and macromolecules. Although a TQT may not be required, it is well known that many proteins do have QTc and other cardiovascular effects, and regulators do still expect submission of some ECG data for large molecules. A further clarification concerning what type of ECG data is expected would be helpful.
In summary, the latest Q&A document further refines our understanding of the regulatory pathways for evaluating the proarrhythmic potential of new drugs. As always, there are always further issues which may still require additional clarification, and we await future releases from the E14 IWG.
For more information on TQT studies, contact ERT here.