Is The Thorough QT Study Still Required?
Recent proposals are in play which may have an impact on the future of the Thorough QT (TQT) study and on the evaluation of cardiac safety for new drugs. ERT is involved in the conversation with regulators and with the evaluation of these new proposals, and we can guide your team through this evolving regulatory landscape. Here, we aim to provide answers to some of the questions we often receive on the current status and future of this cardiac safety requirement.
What is driving the effort to replace the TQT study?
Since 2005, ICH E14 has been successful in that no drug developed under its guidance has been withdrawn for QT prolongation or Torsade de Pointes (TdP). However, the unintended consequence of E14 is that too many drugs, some of which may be safe and effective, are dropped early in development due to minor QT concerns or equivocal preclinical signals. In response, over the past few years the FDA, other regulatory bodies, and pharma have been exploring options to replace TQTs with preclinical testing or with data collected during standard Phase I trials.
What are the current FDA proposals to replace TQT studies?
There are two proposals at different stages of development. The first is to use increased preclinical testing – the CiPA Proposal (Comprehensive in Vitro Proarrhythmia Assay) – to replace the TQT. We anticipate that it will be at least several years before we know if this will be an effective replacement for assessing cardiac safety during drug development. The second proposal would substitute intense ECG collection in SAD/MAD Phase I for the TQT – the CSRC/IQ Consortium proposal. Since the cohort sizes in typical Phase I trials are small, the typical analysis of QTc changes by time point will not be very useful. Instead, this strategy would use concentration effect modeling (CEM), or PK-PD assessments, to detect drug induced increases in QTc. A CSRC/IQ Consortium trial recently tested whether ECG and PK-PD data collected in Phase I could generate data equivalent to a TQT. The trial design was similar to a typical SAD study, and the FDA contributed to the trial and selected six drugs to be tested: five known QT prolongers as well as one non-QT prolonger. In December 2014, the CSRC/IQ Consortium announced the successful results of the trial. PK-PD modeling was able to successfully generate data for these 6 drugs which were very similar to the results of TQT studies. These findings raise the possibility that, depending on the regulatory response, Phase I ECG and PK-PD data may be permitted to replace a TQT study in the future.
Has ICH E14 changed to allow TQT waivers based on intense ECG PK-PD data from Phase I trials?
Regulatory authorities have not yet approved a change to ICH E14, but the ICH E14 Working Group has already begun to review the recent trial and proposal. If approved, this is a very exciting potential opportunity for our industry. Data could be collected in standard Phase I trials with minimal change to current practices, and in many cases could eliminate the need for a dedicated TQT study. Adding Holter ECG collection to a Phase I study is inexpensive, and this change could reduce individual study costs dramatically. Cardiac safety could potentially be determined much earlier in drug development, allowing sponsors to prioritize development efforts and make faster decisions on investments. Most importantly, we will develop more life-saving and life-enhancing medical products for the patients who need them.
Are there any issues with replacing the TQT with intense ECG PK-PD data from Phase I trials? Will this apply to all drugs?
There are many open issues to navigate with this potential regulatory change, and the Phase I strategy may not work for every compound. False positive and false negative rates are as yet unknown, and there is also potential regulatory concern about the lack of positive controls. Larger cohorts and trial design changes in Phase I might potentially be needed. There are also questions about whether this design will be effective for drugs with active metabolites (PK-PD assessment of the parent compound will not necessarily detect QTc effects of metabolites) or unusual pharmacokinetics (which often will not be understood at the time of Phase I studies). There are number of other specific dimensions to consider, and ERT would like to review the whole range of issues and options with your team to fully optimize your next cardiac safety trial.
Can ERT implement the proposed new approach?
Yes, ERT can support this immediately. Our cardiology experts with decades of trial design and regulatory experience will work with you to develop the most cost-effective and secure strategy for your next trial. We have successfully conducted over 1,000 Phase I cardiac safety studies, and our precise, validated semi-auto analysis with industry leading SD of 5 to 8 ms delivers the highest data quality. ERT has performed intense ECG collection as well as PK-PD analysis for many Phase I trials since 2000, and our expertise, innovation, and integration in cardiac safety centralization are unparalleled.
The CSRC/IQ Consortium trial utilized “high-precision QT analysis”. Is this the preferred or only accepted ECG methodology for Phase I intense ECGs? No, the trial employed a methodology utilized by only a single ECG core lab, and other methodologies are just as effective, if not more so, for intense ECG PK-PD collection and analysis in Phase I. The CSRC stated in a clarification letter published to members and industry in January 2015 that they do not endorse any specific technology or ECG methodology. Regulatory bodies like the FDA, EMA, Health Canada, and PMDA similarly do not endorse any vendor’s technology or methodology.
Is ERT’s approach as precise as “high-precision QT analysis”?
Yes. “High-precision QT analysis” is based on the COMPAS system, a proprietary algorithm developed in 1990s/early 2000s. It calls for 10 ECGs to be collected per time point and for automated measurements. 3 ECGs per time point is the industry standard, and published data suggests that beyond 3-5 replicates, there is little additional reduction in variability, but, of course, higher cost. ERT recommends that measurements be performed with a semi-automated analysis methodology that leverages an algorithm for initial caliper placements and then human adjudication of all measurements. Semi-automated measurements are currently the industry standard. ERT recommends human review and adjudication of all ECGs, and ERT’s precise semi-auto analysis with industry leading SD of 5 to 8 ms in Phase I cardiac safety studies was used to support 20% of all new drug approvals in 2014 alone.
Where can I learn more?
You can view a recently recorded webinar on the future of the TQT – or schedule an information session with an ERT cardiologist to review the whole range of issues and options to optimize your next cardiac safety trial.