fno
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2020-01-22 15:38

Posting: # 21078
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 FDA: required BE between early phase and Phase 3 formulations? [Regulatives / Guidelines]

Dear All,

Sorry for the naive and quite basic question, but I did not succeed in finding a clear and definite answer in any of the FDA guidances :confused::

Is FDA requiring a formal BE demonstration for bridging the early phase with the Phase 3 formulations?
If so, what would be the required actions in case the Phase 3 formulation is not perfectly bioequivalent to the previously used formulation?

Many thanks in advance!

Kind regards,
Fabrice
Helmut
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Vienna, Austria,
2020-01-22 16:15

@ fno
Posting: # 21079
Views: 379
 

 no BE between early phase and Phase 3 formulations

Hi Fabrice,

» Is FDA requiring a formal BE demonstration for bridging the early phase with the Phase 3 formulations?
» If so, what would be the required actions in case the Phase 3 formulation is not perfectly bioequivalent to the previously used formulation?

Without digging into guidelines: No. What we have in Phase I/II is sometimes not what I would call a ‘formulation’ in the biopharmaceutical sense at all. Anything goes: Manually filled capsules, lab-scale tablet-presses, etc. Doesn’t matter because we are interested in PK (I) and safety (II). Once you move to phase III you are bound to cGMP (though still in pilot-scale). Only when you move from III to the to be marketed formulation, the applicable SUPAC guidance (IR, MR, SS) cut in and very likely you need a BE study.

Cheers,
Helmut Schütz
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fno
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Belgium,
2020-01-22 17:11

@ Helmut
Posting: # 21080
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 no BE between early phase and Phase 3 formulations

Thanks Helmut for your feed-back!

» Without digging into guidelines: No. What we have in Phase I/II is sometimes not what I would call a ‘formulation’ in the biopharmaceutical sense at all. Anything goes: Manually filled capsules, lab-scale tablet-presses, etc.

Indeed.

» Doesn’t matter because we are interested in PK (I) and safety (II).

OK but then how to justify in the dossier the extrapolation of some early phase outcomes, e.g. a food effect or an efficacy and/or safety exposure signal... should these key findings be evaluated/demonstrated again with the final formulation?

» Once you move to phase III you are bound to cGMP (though still in pilot-scale). Only when you move from III to the to be marketed formulation, the applicable SUPAC guidance (IR, MR, SS) cut in and very likely you need a BE study.

Yep.

Thank you!

Kind regards,
Fabrice
Helmut
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Vienna, Austria,
2020-01-23 11:59

@ fno
Posting: # 21082
Views: 324
 

 relax

Hi Fabrice,

» » Doesn’t matter because we are interested in PK (I) and safety (II).
»
» OK but then how to justify in the dossier the extrapolation of some early phase outcomes, e.g. a food effect or an efficacy and/or safety exposure signal... should these key findings be evaluated/demonstrated again with the final formulation?

An example: The NDA of idelalisib. A lot of Phase I/II studies (women/men, Japanese/Caucasian, food effect, DDIs, renal/hepatic impairment) were performed in 6 (six!) to 12 subjects with early formulations.
There was also a study comparing formulations (n = 15, extremely underpowered for the x̃ CV of 29% in earlier studies). Some comparisons failed (e.g., 90% CI of Cmax 106–153%). Funny:

2.5.2.2 What are the safety or efficacy issues, if any, for BE studies that fail to meet the 90% CI using equivalence limits of 80–125%?
None. The exposure for the different drug products is similar.

Quoting nobody: It’s originator, stupid!

Since idelalisib is in BCS II (where dissolution cannot predict in vivo performance), the FDA lamented about later manufacturing changes but accepted the package at the end of the day.

Cheers,
Helmut Schütz
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fno
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Belgium,
2020-01-23 14:48
(edited by fno on 2020-01-23 16:16)

@ Helmut
Posting: # 21084
Views: 307
 

 Thanks!

:ok:

Kind regards,
Fabrice
Achievwin
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US,
2020-01-27 20:06

@ fno
Posting: # 21087
Views: 177
 

 FDA: required BE between early phase and Phase 3 formulations?

Typically it is not needed, because your approval is based on Two identical Phase III studies, all early development studies (such as FIH, ADME, DDI Dose escalation etc.) are conducted on a preliminary dosage form which leads to refinement of the dosage form at the end of Phase 2 program typically companies present the data to regulatory agencies and formalize the dosage form and Phase 3 study design. Work done for Phase 3 programs forms pivotal/basis for NDA approval. Sponsor routinely performs a relative BA study (not a must) between the Phase 2 dosage form and phase III IMP do document only minor changes in formulation exist as a process optimization and these changes have no consequence on the bioavailability. IMHO it is a risk mitigation step for the NDA.

Hope other members agree with my reasoning.

Best

Achievwin
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