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Dear Kaushal
It is permissible for a firm to do the in vivo BE study against a
lower strength than what is recommended. However, if the firm ever
chooses to market the higher strength another in vivo BE study must be
performed.
Regards
Kazipeta Chander
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The following message was posted to: PharmPK
Kazipeta,
This is not always the case. For example, with Wellbutrin BE studies
were performed using the 150 mg dose strength. These studies supported
the marketing of the 300 mg dose strength for the generic. The FDA
stated that this approach was acceptable based due to safety concerns
with the use of the higher strength in normal volunteers. Details can
be found at http://www.fda.gov/CDER/drug/infopage/bupropion/TE_review.htm
.. Below is a brief extract from the webpage.
*What was the basis for approval of Teva's generic bupropion XL*?
The basis for approval of Teva's bupropion XL was that there was no
significant difference in the rate and extent of absorption as
measured by the plasma bupropion concentrations between 150 mg of the
Teva XL product and 150 mg of Wellbutrin XL. Because of the potential
risk of seizures at higher doses, the 300 mg strength was not studied.
This practice is used when evaluating the pharmacokinetic profile of a
drug in normal volunteers, especially when a drug's adverse effects
increase with dose. The pharmacokinetic profile is not expected to
differ between 300 mg and 150 mg doses of bupropion.
Regards
Mark Milton
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Hi Chander,
Please download the guidance from
http://www.fda.gov/cder/guidance/4964dft.pdf
and goto page 14 (Page 17 of 27 in PDF document). It says
"For an ANDA, conducting an in vivo study on a strength that is not
the highest may be appropriate for reasons of safety, subject to
approval by the Division of Bioequivalence, Office of Generic Drugs,
and provided that the following conditions are met:
.. Linear elimination kinetics has been shown over the therapeutic dose
range.
.. The higher strengths of the test and reference products are
proportionally similar to their corresponding lower strength.
.. Comparative dissolution testing on the higher strength of the test
and reference products is submitted and found to be appropriate."
You can also write to FDA on this matter and seek their directions.
Hope that helps!
Dr. Gagandeep Singh
Manager-Consulting
Cognizant Business Consulting - Lifesciences
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Hi Chander
The response from FDA is absolutely correct - I personally believe
since safety profile, elimination data & dissolution profile of higher
strengths were not mentioned in your communication to FDA, hence the
answer FDA gave with respect to your question, was right. I cannot
comment any more since molecule name has not been disclosed. However,
I would still advise you to-
.. Consult your clinical team if the highest dose is safe enough to be
given to subjects
.. Do some market research if some other company has done trials on
highest strength and also if the trial has been approved. In this
case, it would mean that the highest dose was safe enough to be
administered in BE trial and it would mean that FDA may not waive off
the in-vivo tests on highest dose based on the 'safety' reasons.
The only way you could probably go in for a waiver would be to do some
tests in lab & generate your own data with respect to the 3 bullet
points on Page 14 of document I mentioned in previous email, justify
facts and try to get waiver on higher strength. If this cannot be
done, pivotal studies will have to be done on highest strength as
mentioned in the email response from FDA.
Regards
Dr. Gagandeep Singh
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