Shuanghe
★★  

Spain,
2019-11-25 13:05

Posting: # 20865
Views: 491
 

 necessity of retention samples for pilot BE study [Regulatives / Guidelines]

Dear All,

I'm surprised that among so many questions with regard to retention samples that have been asked in the forum, I couldn't find the answer that I'm looking for. My question is not related to the quantity, but to the necessity for pilot BE.

According to FDA's guidance (21CRF), sufficient retention samples (5 times complete analysis or 300 units etc ) should be kept in CRO where the BE studies were conducted. The guidance doesn't mention if this is for pilot or pivotal. Obviously, you need this for pivotal BE, but what about pilot BE?

Our practice (SOP) is to send sufficient retention samples for any BE, regardless of pilot or pivotal. However, recently, we had a problem with one Indian CRO. I was told by them that DCGI might problem with this large than necessary amount of product for pilot BE. We cited the FDA's guidance but they still refuse it.

So this is the background of my asking here. What are your opinions and experiences? Should it be sent for pilot BE? Thanks.

All the best,
Shuanghe
Ohlbe
★★★

France,
2019-11-25 15:16

@ Shuanghe
Posting: # 20866
Views: 229
 

 necessity of retention samples for pilot BE study

Dear Shuanghe,

» I'm surprised that among so many questions with regard to retention samples that have been asked in the forum, I couldn't find the answer that I'm looking for. My question is not related to the quantity, but to the necessity for pilot BE.

If I read 21CFR320.63 correctly, it says:

The applicant of an abbreviated application or a supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application.

As pilot trials are not "required for approval", I would understand that retention samples are not needed for pilot studies. But I'm not a specialist of FDA regulations and John may have a different interpretation.

Regards
Ohlbe
Shuanghe
★★  

Spain,
2019-11-25 18:00

@ Ohlbe
Posting: # 20868
Views: 213
 

 necessity of retention samples for pilot BE study

Dear Ohlbe,

» As pilot trials are not "required for approval", I would understand that retention samples are not needed for pilot studies. But I'm not a specialist of FDA regulations and John may have a different interpretation.

Thanks! That's certainly one standpoint to look at the regulatory requirement, and it make sense to me. I guess that I missed this point when I read the CFR. Let's see what else we can have in this forum.

All the best,
Shuanghe
ElMaestro
★★★

Belgium?,
2019-11-25 17:38

@ Shuanghe
Posting: # 20867
Views: 218
 

 necessity of retention samples for pilot BE study

It is a great question,

thanks Shuanghe for asking it.



» According to FDA's guidance (21CRF), sufficient retention samples (5 times complete analysis or 300 units etc ) should be kept in CRO where the BE studies were conducted. The guidance doesn't mention if this is for pilot or pivotal. Obviously, you need this for pivotal BE, but what about pilot BE?

I have been wondering something along exactly the same lines recently.

My angle on this was related. FDA recently issued a PSG for Beclo/Calcipotriol introducing the need for a pilot trial.
The idea to have a pilot trial relates to a guidance which is roughly 16 bilion years old but which still stands.

It is not clear, given exactly the wording quoted by Ohlbe what status to give to the pilot. On one hand the pilot does not give pivotall proof of BE, on the other hand it does seem required when you read the PSG. One can of course go into the semantics and discussion the practical meaning of "required" and "recommended" etc. I will abstain from doing so - my experience with such discussion is not so good. To me, if it is in a FDA BE guidance (PSG or not, draft or not) to do X, Y and Z, then I do X, Y and Z without shortcuts unless I have a tremendously good reason from FDA not do to do so. Opinions on X, Y and Z from any entity which is not FDA will on those matters be less important for the decision-making.

So it does create an unclear situation. I'd do full retention, switch CRO if necessary in the absence of a controlled correspondence or FDA communication to the opposite.

In perspective: Is the Beclo/Calcip guidance the first one mentioning the need (or whatever it is) for a pilot?

I could be wrong, but...
Best regards,
ElMaestro
Shuanghe
★★  

Spain,
2019-11-25 18:42

@ ElMaestro
Posting: # 20870
Views: 209
 

 necessity of retention samples for pilot BE study

Thanks, ElMaestro!

» It is not clear, given exactly the wording quoted by Ohlbe what status to give to the pilot. On one hand the pilot does not give pivotall proof of BE, on the other hand it does seem required when you read the PSG.

In this specific case, I would ship retention samples for both pilot and pivotal BE.

To generalize it a little bit, I probably would send retention samples for pilot BE for all topic dermatologic corticosteroids for which vasoconstrictor study is required because, as mentioned in the guidance for "Topical Dermatological Corticosteroids: In Vivo Bioequivalence", the objective of the pilot for this type of the study is to "define the appropriate parameters for the pivotal study" due to the variable dose duration-response characteristics. Since the design of the pivotal BE depend highly on the pilot study, it make sense to treat the pilot specially (don't know how to put it in words but you get what I meant to say).

For other drugs, pilot BE will help you to fine tune the blood sampling, check/validate the bioanalytical method etc. So it helps you to make decisions (e.g., go to pivotal with the same formulation or modify the formulation), but in general, it won't define the parameters of the pivotal BE as mentioned in the topic corticosteroids guidance.

» One can of course go into the semantics and discussion the practical meaning of "required" and "recommended" etc.

No, I won't go there. :-D

» To me, if it is in a FDA BE guidance (PSG or not, draft or not) to do X, Y and Z, then I do X, Y and Z without shortcuts unless I have a tremendously good reason from FDA not do to do so.

Completely agree. The problem is that, in this case, there's no clear requirement. We don't know if there's X/Y/Z.

» I'd do full retention, switch CRO if necessary in the absence of a controlled correspondence or FDA communication to the opposite.

I'm sure I can talk with CRO and push a bit more, maybe they'll agree with the amount. Change CRO is also an option.

However, I would like to know the general consensus on this, if there's any, so I can improve the internal procedure (e.g. our SOP) with this regard.

» In perspective: Is the Beclo/Calcip guidance the first one mentioning the need (or whatever it is) for a pilot?

No, I don't think so. There are quite a lot PSG require pilot, almost all are for vasoconstrictor study, e.g., Clobetasol propionate, Fluticasone propionate , etc.

All the best,
Shuanghe
nobody
nothing

2019-11-26 10:11

@ ElMaestro
Posting: # 20872
Views: 166
 

 necessity of retention samples for pilot BE study

» My angle on this was related. FDA recently issued a PSG for Beclo/Calcipotriol introducing the need for a pilot trial.

This is this occult skin bleaching (vasocontrictor) test, here you don't "ship" any samples at all.

Ladies, these backup samples are for reproducing results in case the primary analysis is fishy. And to stop labs from making up studies and results completely (with mixed results on this part). I would keep this in mind when planning a trial.

If you are in doubt, start a controlled correspondence with the-one-not-to-be-named (aka USA-FDA-Trump-whatever...)

Kindest regards, nobody
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