Helmut
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Vienna, Austria,
2010-05-20 18:53
(5061 d 04:10 ago)

Posting: # 5357
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 Two-Stage Sequential Designs [Two-Stage / GS Designs]

Dear all,

yesterday I talked to Barbarba Davit (Acting Director FDA/CDER/OGD) at the BA/BE-conference in Ljubljana. FDA will accept studies performed according to the method proposed by Potvin et al. (2008). :ok:

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yjlee168
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Kaohsiung, Taiwan,
2010-05-20 23:28
(5060 d 23:35 ago)

@ Helmut
Posting: # 5358
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 Two-Stage Sequential Designs

Dear Helmut,

Thanks for your great news. But you say FDA will accept... not now? Potvin et al. (2008) said "...the FDA has accepted studies with designs like those considered here..." (p.259) in their article.

All the best,
-- Yung-jin Lee
bear v2.9.1:- created by Hsin-ya Lee & Yung-jin Lee
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Helmut
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2010-05-21 03:06
(5060 d 19:58 ago)

@ yjlee168
Posting: # 5361
Views: 14,440
 

 Two-Stage Sequential Designs

Dear bears!

Language is a virus.*

❝ [...] you say FDA will accept... not now?


"Will accept" is as correct as "would have already accepted" in the past – but since not a single study (!) was submitted to the FDA until now, Barbara talked about the future. She was actually somehow surprised that nobody did so until now. She also pointed out that Donald Schuirmann is one of the coauthors of the paper – so FDA is pretty confident with the applicability. On the other hand they recently received a study based on the original work of Pocock (1977)…

❝ Potvin et al. (2008) said "...the FDA has accepted studies with designs like those considered here..." (p.259) in their article.


Also asked and confirmed. :-)



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d_labes
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Berlin, Germany,
2010-06-15 18:02
(5035 d 05:02 ago)

@ Helmut
Posting: # 5520
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 EMA: Two-Stage Sequential Designs

Dear Helmut, dear all!

I have heard some rumor that the Potvin design C may not accepted by the EMA.
Especially the unpenalized stop (without alpha spending) in the first stage if power was demonstrated >80%.

Any comments from the participants of the EGA meeting (aka Klagemauer)?

Regards,

Detlew
Helmut
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2010-06-15 18:23
(5035 d 04:41 ago)

@ d_labes
Posting: # 5522
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 EMA: Two-Stage Sequential Designs

Dear D. Labes!

❝ I have heard some rumor that the Potvin design C may not accepted by the EMA.

❝ Especially the unpenalized stop (without alpha spending) in the first stage if power was demonstrated >80%.

❝ Any comments from the participants of the EGA meeting (aka Klagemauer)?


Hhm, my ears were full of the screams of the desperate there and then.

Only my personal experience with two studies so far. Both protocols were approved by IECs in Berlin and without any questions concerning the method by the BfArM. I specified the method in great detail (including a graphical presentation of the decision tree) and made clear that the patient’s risk is preserved.
My interpretation of the GL calls for an α-correction only if two stages are performed and data pooled.

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The Outlaw Torn
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Europe,
2011-10-20 12:30
(4543 d 10:34 ago)

@ Helmut
Posting: # 7524
Views: 13,669
 

 EMA: Two-Stage Sequential Designs

Hi Helmut,

Do you have any updates to share about these submissions?

Has any authority commented on the lack of a penalty in stage one in case of successful conclusion (BE obtained)?

Any wisdom you can part with would be greatly appreciated.

Thanks.
Helmut
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Vienna, Austria,
2011-10-21 17:01
(4542 d 06:03 ago)

@ The Outlaw Torn
Posting: # 7529
Views: 13,867
 

 EMA: Two-Stage Sequential Designs

Dear Outlaw Torn!

❝ Do you have any updates to share about these submissions?


❝ Has any authority commented on the lack of a penalty in stage one in case of successful conclusion (BE obtained)?


One product (=one study) was approved by the German BfArM June this year (submitted May 2010). Two other studies (different drug) were submitted in the meantime. All studies did not go into stage 2 and no α-adjustment was performed (according to the protocol: Potvin’s Method C, power >80; 90% confidence intervals).

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ElMaestro
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Denmark,
2011-10-21 17:23
(4542 d 05:41 ago)

@ Helmut
Posting: # 7530
Views: 13,569
 

 PAR?

Ahoy HS,

❝ One product (=one study) was approved by the German BfArM June this year.


Do you have a link to a PAR for this product?

Best regards,
EM.
Helmut
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2011-10-21 18:02
(4542 d 05:01 ago)

@ ElMaestro
Posting: # 7531
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 PAR not yet

Dear ElMaestro!

❝ ❝ One product (=one study) was approved by the German BfArM June this year (submitted May 2010).


❝ Do you have a link to a PAR for this product?


Not yet. If you go to PharmNet.Bund (in German only) > Recherche für Fachkreise > at the bottom of the new page ❝ akzeptieren » > Suche nach Attentin in Arzneimittelname. At the bottom ❝ los » > click on "Freie Infos" at the end, you will get a new page displaying
Pub. Assessment Report
(nicht vorhanden) = not existent
SmPC (in German) here.

So you have to believe me that the study was performed as mentioned above – until the product passes MRP. ;-)

This is a strange system anyway. I could not find PARs of other products (where Germany was the RMS) and the PAR is available e.g. at HMA.

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The Outlaw Torn
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Europe,
2011-10-25 10:57
(4538 d 12:07 ago)

@ Helmut
Posting: # 7541
Views: 13,504
 

 PAR not yet

Hi Helmut,

Sorry for the delay (CPhI stuff) and thanks for the info.

We are involved in a project in which the CRO has proposed this study approach. My feedback was basically the same or similar (would I be ostracized if I said "essentially similar"?) to yours—as long as the consumer risk is preserved, I don't see why it wouldn't be okay to stop without penalty after the first stage if the BE study is successful (Potvin method C).

I'll make sure the CRO provides adequate justification in the protocol. Thanks for the feedback. If I get feedback from the authorities on this approach later on, I'll pass it on.
The Outlaw Torn
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Europe,
2011-10-27 13:07
(4536 d 09:57 ago)

@ The Outlaw Torn
Posting: # 7551
Views: 13,874
 

 PAR not yet

Hello all,

We provided our protocol to a central European country and this is what they responded about Potvin method C:

“Method C” as proposed in this publication is not acceptable, as type I error is not controlled on the 5% level and alternative methods securing type I error control are available.

They go on to suggest method B because "The authors demonstrate by simulations that the power of this method is only slightly lower than for “Method C”, resulting in comparable mean total number of subjects."

Any comments?

Thanks.
d_labes
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Berlin, Germany,
2011-10-27 15:16
(4536 d 07:48 ago)

@ The Outlaw Torn
Posting: # 7553
Views: 13,436
 

 Potvin C not acceptable!

Dear Outlaw!

❝ We provided our protocol to a central European country and this is what they responded about Potvin method C:


“Method C” as proposed in this publication is not acceptable, as type I error is not controlled on the 5% level and alternative methods securing type I error control are available.


Regulators are a strange bunch :-D.
Seems they (whoever that is) have taken the 5% literally and do not accept the empirical overall alpha values in method C which are slightly above 5% around CV = 10 to 20%.
Potvin et al. have pointed out clearly that the excess is not at least due to the simulation methodology and may vanish if the number of simulated studies will be raised. Therefore the authors have decided to take only alpha inflation greater then 5.2% as serious (real).
Seems they have not read this or are "päpstlicher als der Pabst" (They are more Catholic than the pope).

Seems this compared to Helmut's experience is a case of ElMaestros "variable constants" :cool:.

Regards,

Detlew
ElMaestro
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Denmark,
2011-10-27 15:25
(4536 d 07:39 ago)

@ The Outlaw Torn
Posting: # 7554
Views: 13,405
 

 PAR not yet

Hi tOT,

“Method C” as proposed in this publication is not acceptable, as type I error is not controlled on the 5% level and alternative methods securing type I error control are available.


❝ They go on to suggest method B because "The authors demonstrate by simulations that the power of this method is only slightly lower than for “Method C”, resulting in comparable mean total number of subjects."


❝ Any comments?


Difficult.
It's their call, really. To distinguish between the methods in practice I think one needs:
  1. To decide which T/R is realistic. 0.95 is a guess but do you have any idea really apart from dissolution?
  2. You proposed number of subjects in stage 1 (n1).
  3. Futility vs. power at the given T/R and n1 for the entire range of CVs.
All in all that's just not straightforward. Especially not if the true T/R differs from the expectation. That blows the entire approach. Wouldn't it be wonderful to use some kinda meffud that takes te observed T/R from stage 1 into account *cough*cough*?

Sounds to me like you should use method B if you wish to avoid discussion and if in vivo T/R really is 0.95.

Pass or fail!
ElMaestro
The Outlaw Torn
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Europe,
2011-10-31 08:45
(4532 d 13:18 ago)

@ ElMaestro
Posting: # 7562
Views: 13,359
 

 PAR not yet

Hi All,

We are finding more and more that argumentation via common sense is less and less effective as the years go by. The quality of open mindedness and common sense has gone way down (it's become a potential serious risk to public health!). Giving this trend, we have sorta abondoned science and have gone the way of the sheep in just doing what they ask for. We are getting really frustrated about so many things.

For example, on another project we had several member states demanding a BE study for a certain product at a higher strength, while several others are adamant that it is not ethical to conduct such a study in Europe (some national boards have ruled against it). So, in order to have a chance to place our product on the market we have to go across the great pond to conduct this study, eventhough we consider this unethical. Crazy, common-senseless things going on nowadays.

Thanks to all for the feedback.
Helmut
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Vienna, Austria,
2011-10-31 16:04
(4532 d 06:00 ago)

@ The Outlaw Torn
Posting: # 7567
Views: 13,438
 

 No (?) comment :-(

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