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Dear members,
Is it necessary to have similar or very similar kind of formulation(
dose
form) at early phase-I trials of NCE ( we have dry powder suspension) as
to the doses form which is going to be marketed after phase-IV ( planned
for tablet)? It is understood that the availability may change with the
change of doses form.
If yes, then why. If no, then what kind of studies should be done to
address this kind of queries. Is any regulatory agencies/ guidelines
say
any thing about this?
Thanks,
Ruchy
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Dear Ruchi
Ideally the formulation during each phase of clinicla trial should
remain same, but as you mentioned under certain circumstances, change
in formulation is required. If such change in formulation occurs you
have to show that your new formulation is bioequivalent with the
previous old formulation.
Hope this helps
Thanks
Tausif Ahmed
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Ruchi,
It is essential to have the same formulation through Phase I to Phase
III/IV.
In fact, before starting the Phase I the complete stability profiling
of the
NCE formulation has to be generated. This is required by DCGI also.
Scientifically also formulation should not be changed. Because the PK
generated during Phase I study determines the PD during Phase II - III
and
the change in formulation at a later date can alter your profile
completely.
Y.Chugh
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PK and toxicological bridging studies are necessary to demonstrate
equivalence between the formulations.
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I do not agree with the earlier reply at all. If you have a terrible
formulation in Phase 1 you should not live with it in Phase 3. (e.g.,
telling the marketing people that the drug is great but needs TID
dosing will not make the marketing people happy at all). I am sure
there are many times when you want to change the PK part of the PK/PD
relationship after Phase 1 because the dosing profile would not be
marketable. You can run Phase 2 with commercially unfeasible
formulations to see if you get an effect because these subjects know
that this is a trial and are willing to accept a little awkwardness
(eg, 6 tablets/treatment to get the highest dose). While doing Phase 2
the formulations gurus can be busy getting a more marketable
formulation/dose strengths prepared. You can use concentration response
relationships to estimate exposure between the two formulations for MTD
and toxicity purposes.
Where I don't want a change is between Phase III clinical and
commercial formulations (and luckily this doesn't happen often as these
changes are reserved for life cycle management!).
Susan
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Your pivotal studies need to be conducted with the final (commercial)
formulation. A bridging BA/BE study should be performed to compare the
new and the old formulation. If they are significantly different, some
of
the Phase I studies may have to be repeated with the new formulation for
the results to be included in the label (package insert). For example,
if
the bioavailability of the older formulation was very poor, the drug
interaction studies may not be relevant and may have to be repeated.
You
should have a discussion with the regulatory authorities about which
studies you may have to repeat.
Hope this helps,
Varun
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Hello all,
I fully agree with Susan.
Formulations for early clinical phases are cannot always be the same as
the commercial dosage form.
There are at least two reasons:
- the 'commercial dosage form' development is generally led at the same
time as the first clinical trials and formulation scientists must have
all the parameters (including some clinical data) to set up the correct
dosage form.
- phase I formulations and commercial dosage forms do not share the
same philosophy. Phase I formulation is supposed to ensure an optimal
absorption of the drug so that Phase I data appear as the best basis
for other clinical phases. The commercial dosage form is the conclusion
of all these clinical studies but the other main point is that the
commercial dosage form is designed as the marketing department has
decided ...if possible.
Have you ever seen the marketing guy's face when you say that the only
dosage form you can provide him with is a drug suspension ???
Best regards,
Frederic DOC
ex-Pfizer formulation scientist
CEO and consultant
ACRITER Consulting
7 rue montespan
91024 Evry cedex, France
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