Comments on E14 and S7B June guidelines

The ICH E14 guidance contains two points in the \"design\" section (2.1)
that require clarification. First, the guidance indicates that a
"thorough QT/QT~c~ clinical study" (TCS) will be conducted regardless of
the outcome of non-clinical testing. This implies that the clinical
study may be conducted without non-clinical data. Second, the guidance
indicates that if non-clinical data are \"informative enough\" about the
risk of QT prolongation, some regions (presumably Europe, Canada and
Japan) may modify the requirements of the TCS. Thus, there will be
regional differences in the conduct of TCSs that would defeat the
purpose of the ICH.

We believe that non-clinical data must be obtained on all
non-antiarrhythmic drugs before first use in man. Absent these data, the
risk of not knowing that a drug might block hERG and prolong APD at
submicromolar concentrations is simply too great. We also believe that
the results of the non-clinical tests should affect the design of TCSs.
A drug having no hERG, APD or QT signals non-clinically should satisfy a
minimum TCS agreed upon by all ICH regions. A drug having these signals
would be subjected to more stringent TCSs depending on the level of
risk. A drug showing block in the hERG assay but no APD or QT signals
should have a different TCS from a drug showing all three signals.
Furthermore, TCSs should differ depending on the ratio of potency of the
non-clinical signal to effective therapeutic plasma concentration
(Redfern et al, 2003). A drug with a ratio below 30 should have a more
stringent TCS than a drug with a ratio above 100. In summary,
non-clinical studies are necessary before first use in man and
differences among non-clinical results should guide the stringency of
thorough QT/QTc clinical studies that will be done.

It follows that we do not agree with the June 04 S7B guidance statement
indicating that assessment of the risk for delayed ventricular
repolarization and QT interval prolongation *does not* need to be done
prior to first use in humans. This statement conflicts with the S7A
guidance stating that the effect of the test substance on the core
battery systems should be investigated *prior* to first use in humans.
In addition to this conflict between the S7A and S7B guidances, the S7B
guidance contradicts itself in Section 2.4. Initially the guidance
states that "results from S7B non-clinical studies assessing the risk
for delayed ventricular repolarization and QT interval prolongation
generally do not need to be available prior to first administration in
humans;" whereas the last sentence in the same paragraph states that the
"early availability of these data is considered valuable." If the data
are valuable in risk evaluation, they should be collected and analyzed
prior to first use in humans.

Another conflict between the S7A and the S7B is GLP status. The S7A
states that the core battery safety testing should be done following GLP
guidelines. The purpose of the GLP requirement is to enforce a uniformly
high standard of scientific rigor for all submitted data. The S7B does
not mention GLP requirements, implying that a lower standard is
acceptable. This seems unjustified given the high level of concern for
QT risk. Since 21 CFR Part 58 is applicable to all non-clinical data
submitted to the FDA as part of an application, the S7B should require
GLP studies.

A modification to the section in S7A section 2.7.2 dealing with the core
battery and references to S7B on would change the last sentence in
Section 2.7.2 to say "should be evaluated" instead of "should be
considered."