Comments on S7B Step 2 Revision

**[The Nonclinical Evaluation of the Potential for Delayed Ventricular
Repolarisation (QT Interval Prolongation) by Human
Pharmaceuticals]{.underline}**

1\. Based on the current draft of ICH E14 and ICH S7B a thorough QT
study will be required on all NCEs and that nonclinical studies are not
required to support FIH studies. Given this situation there appears to
be no regulatory value in nonclinical data since it is widely accepted
that clinical data 'trumps' nonclinical. Thus the need for ICH S7B as a
guidance document is not justified with the current draft of ICH E14.

2\. The apparent inconsistency in the timing of CV nonclinical studies
between ICH S7A and S7B is troubling and confusing.

ICH S7A states in Section 2.7.2 \"The effects of the test substance on
the cardiovascular system should be assessed appropriately. Blood
pressure, heart rate and the electrocardiogram should be evaluated. In
vivo, in vitro and/or ex vivo evaluations, including methods for
depolarization and conductance abnormalities should also be
considered.\"

Current industrial practice and state of the art CV science would
suggest \"appropriate evaluation of CV risk would include at a minimum
both in vitro hERG and in vivo CV ECG data. However, ICH S7B states in
Section 2.4 \"Results from S7B \...generally do not need to be available
prior to first administration in humans.\"

The impact of GLP also needs to be clarified/considered. If non-GLP hERG
studies and in vivo telemetered studies are used for internal decision
making prior to candidate nomination, these will have to be repeated
because ICH S7A defines the need for GLP compliance and ICH S7B states
the principles of ICHS 7A extend to it. Also, the preamble of the GLP
regulations 21 CFR, 58.3 (d) clearly defines the need for all
nonclinical safety supporting studies to be conducted to the GLP
standard.

3\. The regional differences in opinion about the utility of nonclinical
data are very troubling and conflicts with the underlying principal
harmonization. The consequence of this is that sponsor companies will be
required to conduct extensive nonclinical studies for Europe and Japan
and a thorough QT study for US.

4\. Section 3.1.1 Use of Positive Control \... suggests the use of
representative compound of the same class as a positive control. This
unnecessarily repeats previously published work in animals and thus
represents an inappropriate use of use of animals and conflicts with the
generally accepted principles of animal use in research. This appears
unnecessary if the sponsor can provide historical data to demonstrate
that the selected study protocol has the desired sensitivity to detect
the desired effect.

5\. Line 15: Indicates that when QT interval is prolonged "there is" an
increased risk for arrhythmia. This should read, "may be" since current
data does not support the absolute increase in risk with QT prolongation
of any magnitude and mechanism.

6\. Line 47: Might better read "**[Currently,]{.underline}** the most
common **[known]{.underline}** mechanism for QT interval prolongation
from pharmaceuticals is inhibition of Ikr".

7\. Line 76: The premise of the guidance is to define risk around QT
prolongation. This line brings in models around pro-arrhythmia. Since
this is currently a rapidly developing area and presently there are no
well-accepted and highly predictive models in general use this should
not necessarily be implied as a potential needed evaluation.

8\. Line 83-85: Comment similar to comment for line 47.

9\. Line 93-94: This is not a testing strategy, as it does not outline
what needs to be defined and when and how to apply. It does represent a
pragmatic risk assessment strategy.

10\. Line 152: This would seem to imply that reference agents need to be
incorporated in every assay. This definitely needs to be clarified. Is
the expectation that validation and periodic studies reassessing
"sensitivity" of the assay would suffice or is the intent to have a
reference agent in every study??

11\. Line 181-186: This is somewhat nebulous. Will this encourage the
regulatory expectation of concurrent "positive controls" for all
studies??

12\. Line 214-217: There appears to be somewhat contradictory thoughts
in these lines. States concentration ranges to above maximal estimated
therapeutic exposure and then goes on to indicate that either establish
a dose-response or reach physiochemical limitations. This should be
clarified.

13\. A number of pharmaceutical companies are investing in higher
through put patch clamp technologies e.g. PatchXpress. These approaches
provide exactly the same quality patch clamp data as the manual assay
and therefore should be considered equivalent and therefore acceptable
to ICH 7B. Lines 236 to 239 should not cover these technologies. This
section should be rephrased to refer to the technology rather than the
through put/capacity.