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Hi,
Can someone point me to a commonly accepted definition of "phase Ib"
vs. "phase IIa" vs. "Proof of concept", or whether there is any
regulatory reference on this? It seems to me that these terms are used
quite interchangeably.
Best regards,
Alain Munafo
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The following message was posted to: PharmPK
Dear Alain,
You ask "a good question". IMHO I think that some conformity of usage
is
emerging but their do seem to be many "fuzzy edges". Phase 1a seems to
refer to the first 3 studies which are: a basic first single ascending
dose
tolerability and PK design, a first repeat dose Pk and safety study
and a
fed vs fasting trial. Phase 1b applies to studies that elaborate PD
effects
if not done in 1a or studies that characterise different formulations
especially if begun after Phase 2 has concluded. Some just use the
term 1b
for all volunteer studies done after Phase 1a.
I have noticed some people calling patient studies Phase 1a when
predictable
toxicity precludes a healthy volunteer trial, such as in oncology. They
usually include Proof of Principle all in the same trial so I would have
thought that they should be called Phase 2a because POP is the further
on in
development.
The term Phase 2a includes a POP study but could extend beyond it if
other
small scale studies are needed on a higher or lower dose or an improved
formulation for example. Phase 2b implies a longer duration of dosing to
obtain adequate safety data to embark on a Phase 3 study programme
(Which is
a major investment decision point). Phase 2a also applies to real
pharmacology trials taking place while Phase 3 is going on, such as a
short
term investigation of a PD or PK interaction.
It seems to me that Phase 2 is "What does the drug do in patients?
while
Phase 3 is "Should we market it?" They are separated more by business
and
organisational concerns than clinical or scientific ones.
Hope this helps.
Andrew Sutton
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The following message was posted to: PharmPK
My own impresssion of drug development phases and sub-phases is:
Phase 0 - Non-human in vivo studies supporting first dose in human step
Phase 1 - Tolerability. Single and multiple dose studies with PK
usually and some limited PD (which may only be based on AEs)
Phase 1b - Subjects demonstrate some biomarker or possibly clinical
outcome that could be considered for POC. POC means what is the answer
to the question "Does the drug work?". It is a Yes/No answer used to
confirm the hypothesis that the current prediction of biomarker/outcome
benefit is compatible with the mechanism of action.
Phase II - Effectiveness. Primary goal is to determine if the drug has
a clinical outcome benefit and to establish the dose range. Often
supported with studies of biomarkers. In recent year it has been split
into IIa and IIb.
Phase IIa - Proof of Concept - "Does the drug work?" Confirming study
with yes/no answer. An optimistic (and perhaps optimised!) Phase IIa
design would also try to learn something about the dose-response and
time course of effect in order to inform the design of Phase IIb.
Phase IIb - Dose Ranging. Learning study -- what is size of effect,
what is shape of dose (or conc) response relationship, what is time
course of effect? etc. Learning studies of this type will necessarily
be able to confirm effectiveness and thus have a confirming element.
Phase III - Effectiveness and "Safety" (A euphemism for toxicity). The
primary purpose is to confirm that a proposed marketable dose derived
from Phase II is effective in a wider population and to learn about
adverse effect frequency, timing, relationship to dose etc..
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Hello,
I'm absolutely agree with you, but the principal aim of phases are:
Phase I: safety/tolerability (mainly healthy volunteers)
Phase II: confirm the pharmacological effect (patients)
Phase III: is EFFICACY.
Phase IV: pharmacovigilance
Regards,
Xavier
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The following message was posted to: PharmPK
Hello,
I'm absolutely agree with you, but the principal aim of phases are:
Phase I: safety/tolerability (mainly healthy volunteers) Phase II:
confirm the pharmacological effect (patients) Phase III: is EFFICACY.
Phase IV: pharmacovigilance
Regards,
Xavier Liogier d'Ardhuy, PhD
PDMP, Clinical Pharmacology
Bdg 15, Office 54
F. Hoffmann-La Roche
CH-4070 Basel, Switzerland
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The following message was posted to: PharmPK
"Liogier D'ardhuy, Xavier {PDMP~Basel}" wrote:
>
> I'm absolutely agree with you, but the principal aim of phases are:
> Phase I: safety/tolerability (mainly healthy volunteers)
> Phase II: confirm the pharmacological effect (patients)
> Phase III: is EFFICACY.
> Phase IV: pharmacovigilance
I have to disagree with the use of the term "efficacy" to describe the
principal aim of Phase III.
An FDA discussion of the phases of drug development can be found here:
http://www.fda.gov/cder/guidance/1857fnl.pdf
"Phase III usually is considered to begin with the initiation of
studies in which the primary objective is to demonstrate, or confirm
therapeutic benefit."
In this context therapeutic benefit refers to the balance between
safety and effectiveness:
"Studies in Phase III are designed to confirm the preliminary evidence
accumulated in Phase II that a drug is safe and effective"
Additional information on FDA definitions of efficacy and effectiveness
and relationships to Phases of clinical drug development can be found
here:
http://www.fda.gov/cder/guidance/4856FNL.PDF
"FDA considers all phase 2, phase 3, and phase 4 trials with efficacy
endpoints as trials to test effectiveness."
FDA guidances refer almost all the time to "effectiveness" rather than
"efficacy". There are some instances where the sloppy use of "efficacy"
appears in guidances in a context that means "effectiveness". Efficacy
has a clear pharmacological meaning -- it means the maximum effect of a
drug (and might be estimated by the Emax parameter of a pharmacodynamic
model). The only place I have found an FDA definition of efficacy in a
guidance is in a footnote to the Effectiveness guidance:
http://www.fda.gov/cder/guidance/1397fnl.pdf
"As used in this guidance, the term efficacy refers to the findings in
an adequate and well-controlled clinical trial or the intent of
conducting such a trial and the term effectiveness refers to the
regulatory determination that is made on the basis of clinical efficacy
and other data."
The definition can only be described as bizarre i.e. "efficacy refers
to... the *intent* of conducting a trial"! Dr Bob Temple (FDA) told me
a couple of years ago that "FDA does not have a definition of efficacy"
and I think this footnote confirms it.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Dear all
Lot has been written on this. From sponsors or innovators point of view
I could place following definitions broadly. Of course these are in
addition to those discussed before. The sponsors have to balance the
science and regulaory requirements to support future marketing
strateies.
Phase I: safety/tolerability -Define dosing strategy for further trials
Phase II: Dose response
Phase III: Define place in therapy
Phase IV: pharmacovigilance and consolidate place in therapy
Thanks and regards
Dr.Prashant
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The following message was posted to: PharmPK
Dear Nick,
Sorry for this provoking email, but it was also a way for me (and
probably not only for me) to have a strong demonstration on the
opposition between effectiveness and efficacy.
The other thing is that this discussion does not exist in France (for
french speakers) as no word exists to differentiate "efficacy" and
"effectiveness". However, we have to know that this subtlety exists.
Thank you very much for having spent some times to detail your answer.
Kind regards,
Xavier
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