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Here is a question to the preclinical folks. At what point in
clinical development and under what conditions can you dose humans
longer than your preclinical multiple dose tox studies?
Thank you in advance
Pete bonate
--
Peter Bonate
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As a general rule, if it looks like it is doing the patient
good-compassionate care- and there may be issues if you withhold.
Ed O'Connor, PhD
Technical Director, Immunoanalytical
Tandem Laboratories
115 Silvia Street
West Trenton, New Jersey
609-228-0243
ed.oconnor.at.tandemlabs.com
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Dear Pete
ICH recommend 2 weeks tox for single dose or up to two weeks, one month
tox for one month clinical study, 3 month tox for up to 3 month clinical
study in rodents and non-rodents. Up to 6 months dosing requires 6
months tox in rodent and 9-month tox in non-rodent.
I haven't had that much experience yet but it seems to me that (under
IND) you cannot dose longer in the clinic than for the duration of your
preclinical studies until you finish chronic tox studies, that is
6-month rodent and 9-month non-rodent. Thereafter, ICH guidelines are
not clear but my interpretation is that longer dosing in the clinic
would usually be acceptable once these studies are completed and
toxicity is characterised.
If not under IND, treatment in the clinic may be extended beyond
existing tox studies if closely monitored and reported to regulatory
authority on a frequent basis.
If treatment is cyclical, the duration of each cycle may suffice
depending on each case presumably.
I would also welcome feedback on these issues.
Keith Dredge
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I think Peter's question is as much clinical as pre-clinical. I have
always
worked on the principle that 3 month tox clears the way for 12 month
clinical trials provided that the clinical pharmacology is OK. If the
benefit to patients is unique to the new drug and clinically significant
then you can, even should, continue dosing indefinitely, with
appropriate
safety monitoring of course.
Tox for 1 month only clears the path for 7 days in man
Andrew Sutton
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
URL: www.gcpl.co.uk
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What Keith says is correct in terms of how long you can dose to man
based on duration of tox studies. However, once the 6 month tox in
rodents and 9 month tox in non-rodents are completed, dosing in man can
be extended beyond these time limits.
regards
Brian
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Forum:
Whereas 9 month tox testing has become a routine I don't know of any
hard
data that justifies it vs 6 or even 3 months so I would be glad if
anyone
has some and can share it. If it exists the holistic view is to ask
the
next question, which is whether that toxicology would be detected
routinely
in human trials at an early enough stage to prevent injury to a patient.
Obviously I believe that our safety testing is properly effective in
that
regard but in a forum like this one we might be able to investigate
whether
that is a correct assumption. We might find that there are extra
tests we
should be doing. That would be a safer option in the long term than
relying
on prolonged tests in animals, not to mention speeding up medicines
development and reducing costs.
I know people will point to late toxic effects appearing in humans
such as
QT interval prolongation and cardiac events on NSAIDs but I doubt that 9
month tox would have prevented them. The former would be detected by
doing
the right type of test rather than prolonging the wrong ones. The
latter may
not be a purely toxic effect at all, since those analgesics only have to
fail to provide 24/24 pain relief for risk factors due to the stress of
chronic pain to increase and so affect the prognosis. People in pain get
angry, depressed and fatigued and those are all liable to raise blood
pressures and provoke myocardial infarctions for example.
Thanks
Andrew Sutton
Guildford Clinical Pharmacology Ltd.
www.gcpl.co.uk
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