Regulators Discuss Early QT Assessments

On February 2, 2012, the Cardiac Safety Research Consortium held a meeting “QT Assessment in Early Clinical Development: Can the predictive value be enhanced to be similar to that of a TQT study?” The underlying thought was to see if enough evidence can be gathered to mitigate the need for a TQT study.

Speakers included representatives of the FDA, Health Canada, EMA/MHRA and industry. Representatives from the FDA—Drs. Christine Garnett and Joanne Zhang--spoke about the value of the TQT study and how the data can help keep a drug from entering the market with arrhythmic potential.

The FDA speakers reported that the QT assessment in early Phase I trials (SAD, MAD studies) can clarify some ambiguous results from a formal TQT study, since lower doses, different regimens, different modes of administration are often used in these Phase I programs. The role of concentration modeling (QTc changes from baseline plotted against concentration) was discussed in depth and the FDA speakers so far believe that a QTc shortening or a QTc prolongation signal observed in such trials could be the rationale for a discussion with regulatory agencies in order to obtain a TQT waiver.

The background being that before discussion a potential TQT waiver, there is an internal decision process and at least for a QTc prolongation liability, most often the strategy will be a go/no-go decision. Dr. Zhang extensively discussed the actual limitations of an early QT assessment, in particular the lack of positive control and the small sample size typical for these SAD/MAD studies. But globally, the FDA speakers concluded that it is--in 2012--a useful approach.

The two industry representatives were Corina Dota for Astra Zeneca and Steve Riley on behalf of Pfizer. Dr. Dota confirmed that currently AstraZeneca uses high quality extensive ECG programs associated with SAD and MAD studies, and confirmed that they internally were able to detect some relevant ECG changes despite the small sample size. However, there is not yet at AstraZeneca robust data to support how predictive early QT assessment is, in comparison with a formal TQT study. Dr. Dota also concluded that predictively for Phase I ECG studies in humans should be combined with the research on the productivity for preclinical experiments (the HESI program).

Dr. Riley reported a similar experience at Pfizer, confirming that a high quality database can be obtained in this setting. The consistency between early QT assessment and the TQT is still under evaluation at Pfizer, the negative TQT studies being accurately predicted, whereas the QTc changes from positive TQT trials were not.

It is interesting to note that representative from EMA/MHRA Dr. Prasad attended this CSRC meeting for the first time, whereas the participation of Health Canada Agency has long been established.

Not surprisingly, Dr. Prasad insisted on the key role in Europe of pre-clinical experiments according to the ICHS7B Guidance. Dr. Prasad showed a similar slide to Dr. Garnett on a possible TQT waiver. Pre-clinical data in early clinical studies in humans are always reviewed in parallel, and a consistent "story" could be seen as convincing, but once again mainly in case of a positive signal.

Three “break-out” sessions were conducted:

· Role of Concentration Effect Modeling in Assessing a Drug’s Effect on the QTc Interval

· How Can Assay Sensitivity be Established in Early Clinical Trials without the use of Moxifloxacin

· Can an approach integrating non-clinical and early clinical QT assessment replace the thorough QT study

At the end of the day, no final decisions were made, but further investigation was encouraged.