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Dear All,
Can anyone explain that, three way crossover study comparing one test
product with two reference product from different regulatory is
acceptable
or not?
Thanks in advance.
Regards
Narayana Kumar.
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The following message was posted to: PharmPK
Dear Narayanakumar,
It is possible to do a three way cross over with two different
reference formulations for two different regulatory countries
submission. It is cost effective at the same time number of dropouts
is the main concern.
Please correct me if am wrong.
Regards,
Manukrishnan
Lambda-Chennai
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Dear Narayana,
Yes it can be done, many generic companies having same test product
(intended for different regulatory markets), carry out BE studies in
this way as they are very much cost-effective and time-saving. But
take this risk only if you are pretty much confident about success of
the study. This strategy is generally advisable for drugs with minimum
adverse events so as to minimize number of drop-outs. Also keep in
consideration, that same clinical study requirements are met by both
the regulatory agencies.
Regards,
Neha
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Dear Narayana Kumar,
It is well accepted by different regulatory bodies, even some
companies does the same for submission in two different countries like
US and Europe.
Regards,
Sudipta Basu
Senior Research Scientist (DMPK-Bioanalytical)
Sai Advantium Pharma Ltd.,
Pune - 57.
E-Mail : sudipta.b.at.saiadvantium.com
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The following message was posted to: PharmPK
I agree with Neha, it can be done.
However, we do this generally in the pilot stage. The objective is to
compare two-reference product (usually from different regulatory bodies)
and 1 Test. Two test products (manufactured from two different batches)
compared with one reference product.
If you do in pivotal stage, you run the risk of justifying the
regulatory, if the test product fails against one of the reference
product. You have many risks like drop out, statically considerations
for the design and AEs, washout period, increase drug exposure and
increase duration of study.
Regards,
Yousuf
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Hi Narayana Kumar,
Yeah Regulatory bodies will accept the design. You have to be very
cautious in designing the sequences and sample size according to the
specific regulatory and now a days sponsors are doing in this way to
decrease the cost.
Thank you,
--
Regards,
M.V.G.S.Raghavendra
Biostatistician
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The following message was posted to: PharmPK
Dear Neha,
You stated, "Also keep in consideration, that same clinical study
requirements are met by both the regulatory agencies."
I do not believe that this is true. There have been many studies
conducted with multiple reference products and multiple evaluation
criteria (e.g. Cmax parameter for USA and Canada). The test product
can be evaluated with the each reference product under the specific
conditions of the regulatory body for submission.
I agree with Yousuf. The data and the comparison of the other
reference product will be available for the both regulatory
authorities to view.
Robert Lepage, M.Sc., CCRP
Manager, Biopharmaceutics
Pharma Medica Research Inc.
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Hi All,
What if Test product meets BE standard for one regulatory and fails to
meet for other regulatory. Can BE will be accepted by first
regulatory, since this is a single experiment we have to provide
complete data to regulatory i.e. data of both reference and one test
product.
Also interpretation become complicated when such designs are used for
Highly Variable Drugs.
Regards,
Yogesh Sonawane,
Biostatistician,
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The following message was posted to: PharmPK
Dear Robert,
By saying "Also keep in consideration, that same clinical study
requirements are met by both the regulatory agencies", I meant
requirements as like strength of the formulation, design of study
(replicate/cross-over) etc.
For ex: In Donepezil HCl tabs,
- For US: RLD strength on which BE is reqd is 10 mg, while
- For EU: BE study is generally recommended to be done on 5 mg
strength, due to potential adverse events associated with higher
strength.
I hope I have made my argument clear now.
For the rest of the text as stated by you and Yousuf, I also do agree.
Regards,
Neha Bhandari
Formulation Research Scientist
Jubilant Organosys Ltd.
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Dear All,
Kindly clarify, While conducting three-way cross over BE study
comparing one
test Vs two reference product from different regulatory, the results
shows
that T Vs R1 is Bioequivalent whereas, T Vs R2 is non bioequivalent.
How the regulatory will accept? (Since we have to submit both the
results to
the regulatory)
Thanks in advance.
Regards
Narayana Kumar.
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Dear Friends,
Just to add one more aspect of variability that is observed in highly
variable molecules.
Do anyone have ideas about regulatory fillings where one lot of
innovator product is proven nonbioequivalent to another lot of
innovator product from the same regulatory.
How do regulatory responds to these kind of situations ?
Thanks & Regards,
Vivek M K Dubey
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The following message was posted to: PharmPK
Dear Vivek!
> Just to add one more aspect of variability that is observed in highly
> variable molecules.
> Do anyone have ideas about regulatory fillings where one lot of
> innovator product is proven nonbioequivalent to another lot of
> innovator product from the same regulatory.
> How do regulatory responds to these kind of situations ?
>
The thread (started by Narayana on October 26th) deals with one test and
two reference products in a three way crossover study. Are you talking
about the same thing? The idea of comparing different batches was
discussed at the BioInternational conference in Munich 1994 and
abandoned finally. It never raised from the grave ever since.
I haven't seen such a study myself (in the business since 1980). ;-)
But let's look at your concept:
Comparsion 1: T vs. R (batch 1)
Comparison 2: T vs. R (batch 2)
Comparison 3: R vs. R (batch 1 / batch 2)
If you run comparisons 1 and 2 you will have to adjust the alpha-risk
(i.e., calculate 95% CIs instead of 90% CI) in order to avoid
multiplicity issues. Otherwise the patients' risk will be inflated
(i.e., almost doubles with two simultaneous tests from 0.05 to
1-[1-0.05]^2=0.0975). This is different from the situation where you
compare two references from different regions (let's say US RLD and a
European innovator's product).
Nitpicking terminology: You cann't 'prove bioinequivalence' between
batches. Bioequivalence by definition is comparative bioavailability of
a test product with a reference product. Everything else (calculating
point estimates and CI) is 'comparative BA'. Proven bioinequivalence
means that the confidence interval lies entirely (!) outside the
acceptance range. I have strong doubts that this is possible even for
products with low and highly variable absorption (let's say
bisphosphonates).
Now let's play the devil's advocate. The limits for the release of a
batch based on assayed content are generally +/-5% of declared. R (batch
1) 95% and R (batch 2) 105% - they just 'made' it through. The test
product is a nice one with a potency of 100%. The study should be
powered to demonstrate BE for a point estimate of 95% (i.e., -5% and
1/0.95 ~+5.3%). T/R (batch 1) = 105.3%, and T/R (batch 2) = 95%.
Remember you plan to run three simultaneous tests! Power the study for
alpha/3 (or 96.67% CIs) to keep the adjusted alpha at 1-[1-0.05/3]^3 0.0492<0.05. Fine. But you will fail in the comparison of batches of the
reference (CI outside the acceptance range). Going one step further you
should also consider the analytical variability of the method for batch
release. Both batches may have slipped through only by chance ('true'
contents higher/lower than +/-5% of declared).
So what's your intention of performing such a study? Blaiming the
innovator for inherent variability of the manufacturing process and
release procedures? The same applies to the test product. I don't think
that any ethics committee will aprove such a design.
Regards,
Helmut
-
Ing. Helmut SchAtz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
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My dear,
this would depend on the BE criteria and this will vary regulatory to
regulatory if the molecule is variable.
For normal drugs i don't think there will not be problem with the one
product where it was failed. And once again it is case to case basis.
Regards
Prasad
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