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by Borje Darpo MD PhD
February 5, 2010

The ICH E14 guidance on clinical evaluation of QT prolongation was adopted in May 2005 (1). An Implementation Working Group (IWG) was at the same time formed as recognition that this was an area of evolving science and accordingly there was a need for a continuous dialogue between regulators and industry. An ICH E14 website, to which questions could be submitted, was opened.  Relatively few questions were submitted and it was not until June 2008 that the first Q&A document was released from the IWG (2). The Q&A document discussed 6 questions, including how the ability of a thorough QT (TQT) study to demonstrate a small QT effect should be confirmed by the results of the positive control, how validation of novel technologies, such as automated methods for QT measurements should be undertaken and whether there was a need to blind the positive control, which the IWG concluded was not the case.
Following the endorsement of the E14 in 2005, FDA formed its Interdisciplinary Review Team (IRT), which rapidly gained a lot of experience by advising on and reviewing all thorough QT/QTc (TQT) studies that were submitted to the agency. The IRT is part of the Cardio-Renal Division and has an advisory role to the reviewing divisions. FDA is the only major regulatory agency that has invested resources into a group that has specialized on this topic. The IRT has been actively engaged in a large number of collaborative initiatives together with industry and has to a large extent set the standards for the conduct of the TQT study. With this as a background the IWG wrote the Q&A document, which therefore was a balance between an already established practice and how other regions viewed the same topic. As an example, the IRT had communicated publicly in detail how they wanted new methods for e.g. QT measurement to be validated through the ‘moxifloxacin-response’, i.e. the new method should be able to capture the QTc prolongation by moxifloxacin in a way that was similar to standard, accepted methods. The answer had therefore to be written very general, as is often the case with ICH document that must be endorsed by all 3 regions, and at the same time accommodate the IRT’s definition of validation.
In June 2009 the ICH Steering Committee decided to disband the E14 IWG, close the website and to instead establish an Informal Discussion Group (IDG) with participants from both clinical (E14) and non-clinical disciplines (S7B). The decision was more political than science-based and emanated from sponsors who wanted to increase the relative importance of non-clinical studies and get away from the mandatory request of performing a TQT study for all compounds with systemic availability. The main question that the IDG was asked to look into was therefore whether accumulated experience with safety pharmacology studies and QT assessment in early studies would justify reopening the E14 document to substantially revise the requirement of a TQT study. Even before the first meeting of the group in St Louis in October 2010, it was clear that this idea did not have much support even industry safety pharmacologist; most parties realize that FDA will only move on this topic based on convincing data and no such data have yet been compiled or presented. Based on some on-going, very interesting collaborative initiatives e.g. the ILSI/HESI Proarrhythmia initiative, data may eventually be compiled to support a move in this direction. This was also the conclusion of the St Louis meeting and ICH E14 will consequently not be reopened.
The decision by the ICH Steering Committee to close the IWG group was also somewhat surprising, given that there are many outstanding issues with the E14 guidance on which both sponsors and regulators would benefit from clarification. Several such topics were discussed in St. Louis and the IDG agreed that there is an on-going need for further clarification. A proposal was therefore made that the IDG group would continue to meet and issue answers on relevant questions and this proposal was subsequently endorsed by the ICH Steering Committee. The following questions will therefore be addressed by the group, which will meet again this summer. Since all questions relate to E14, it is not yet confirmed whether non-clinical representatives will participate.

1. Use of concentration-response relationships in a TQT study: FDA routinely performs a concentration effect analysis on all TQT studies in addition to the standard E14 approach. The intention is to clarify the role of this analysis and whether it can be used to support or validate the results of the standard time-matched analysis;
2. Use of concentration-response relationships and alternative designs of Phase I studies to enhance the evaluation of QTc: This is one of the key questions that must be explored to allow a better understanding on how concentration effect modeling of pooled early studies can provide a sufficiently precise estimate of the QTc effect of a drug to replace the TQT study. Another key component , which can be brought forward as experience is being gained,  is how to ensure that early studies have a sufficiently high sensitivity to capture small QTc effect;
3. Enhanced clarity around gender; It has been repeatedly demonstrated that women are at a higher risk than men for proarrhythmias associated with QTc prolongation. Despite this, there is little to support a gender difference in the degree of QTc prolongation induced by a drug. In line with this, the Q&A document from 2008, states that males or females can be used in the TQT study. Although there seems to be consensus on this topic, some parties advocate that this can be more clearly expressed.
4. Approach to validating new technologies for ECG acquisition and analysis (automated interpretation of intervals); This is also a topic that is quite extensively discussed in the Q&A document from 2008, in which it is described how new methods can be validated using the approach that has been advocated by the FDA (see above). It is therefore not fully clear why this question is being raised again and somewhat difficult to see how an answer can be made more specific;
5. Clarification of approach to evaluating adequacy of HR correction: This will be a difficult challenge for the IDG group to address. Based on accumulated experience from TQT studies, there is a broad, scientific agreement that individualized QTc, derived from the subject in the supine, resting state, does not provide an adequate correction for drugs with intrinsic effect on the heart rate. In contrast, there is no consensus on which methodology among several possible, such as QT beat-to-beat, Holter-bin, ‘optimized QTcI’ or concentration-effect modeling with HR as a covariate, would be the best. In addition, there are not much of comparisons across methods in the public domain, as of yet. The question seems to be prematurely brought to the ICH level but can likely be more effectively discussed within a year, pending comparative data.
6. Clarification of approach to evaluating QTc in late stage clinical development: The question is broadly phrased but the intention seems to be more limited in scope: The objective is to give some examples on how clinical QT assessment can be designed in late-stage studies when the TQT study is positive.

The result of the ICH St. Louis meeting is therefore that an expert group with the mission to issue Q&A document(s) with further clarification to the E14 guidance is reinstituted. If successfully managed, this can provide both industry and regulators with useful advice.