Bioequivalence and Bioavailability Forum • Rant…

Helmut
★★★

Vienna, Austria,
2013-10-29 16:52
(4200 d 03:00 ago)

Posting: # 11805
Views: 8,669

Rant… [Off Topic]

To whom it may concern!

Not only in the forum but in my daily work as a consultant I’m increasingly often confronted with “creative” study designs where the underlying statistical methodology is either dubious or currently nonexistent at all. Just to name a few:

“Two-stage replicate designs” intended for reference-scaling. Method? Patient’s risk?
Replicate designs with more than two treatments. Method?
Futility rules in two-stage designs. Power?
Two-stage designs for parallel groups. Heteroscedasticity? Patient’s risk? Power?
Planning a pivotal study based on a single published CV…

Rather scaring in many cases doubts arise when the study is already underway. How is that possible? Were IECs/IRBs and regulators sleeping as well? In many cases it turned out that people designing those studies had ~~limited~~ no knowledge about existing methods, their underlying assumptions/limitations and/or purposes. “Classical” examples are blindly following FDA’s partial replicate design or believing that the 94.12% confidence interval is applicable to all two-stage designs (aka Pocock’ natural constant α 0.0294). When asked a common answer is “We planned to evaluate the study with SAS…”. Bingo! It also often unfolds that their main sources of information are guidelines, presentations found on the internet, or forum posts / blogs.
Only a minority might have read original publications beyond their abstracts.

To call the statistician after the experiment is done
may be no more than asking him to perform a postmortem examination:
he may be able to say what the experiment died of. RA Fisher

Amazingly these (Internet-Generation?) attitudes are not limited to people working in the industry but to regulators as well. Recently I received a question from an ASEAN-assessor which boiled down to:

“A generic product has demonstrated bioequivalence in a well-powered in vivo study. However, the formulation failed to show f₂ ≥50 in all p_H-values tested. Can I still accept the application?”

—

SCNR,
Helmut (the grumpy old man)

Profile «accessible to registered users only»
The quality of responses received is directly proportional to the quality of the question asked. ☼
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jag009
★★★

NJ,
2013-10-29 17:42
(4200 d 02:10 ago)

@ Helmut
Posting: # 11806
Views: 7,473

Rant…

Post reply

Hi Helmut!

Yes #&%@! No I am not a consultant but I've gotten similar questions from other people too.

❝ Recently I received a question from an ASEAN-assessor which boiled down to:

Are you serious?

John

Helmut
★★★

Vienna, Austria,
2013-10-29 17:51
(4200 d 02:02 ago)

@ jag009
Posting: # 11807
Views: 7,558

Rant…

Post reply

Hi John,

❝ I've gotten similar questions from other people too.

What makes me angry is that these guys run studies which nobody on this planet can evaluate. They don’t give a damn feeding drugs to volunteers. Would they take them themselves?

❝ ❝ Recently I received a question from an ASEAN-assessor…

❝

❝ Are you serious?

Absolutely.
I briefly outlined the underlying concept of bioequivalence (in vivo > in vitro), referred to the respective section of his own country’s guideline (in vitro similarity only for biowaivers – which was not the case here), gave an overview of the BCS and its applicability, :blahblah:

…

Took me an hour. Wasn’t even worth a “Thank you”…

This forum is an information sink. Some posters are the interstellar gas and others black holes.

────────────────────────────────────────────────

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Helmut          2885    0.85        24.86       

ElMaestro        813    0.42         7.01       

D. Labes         777    0.37         6.70       

Ohlbe            587    0.24         5.06       

John             413    0.67         3.56       

Dr. Dan          270    0.19         2.33       

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Jaime R          171    0.06         1.47       

Dr. Gunasakaran  153    0.12         1.32       

Martin           118    0.06         1.02       

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∑               6429                55.40       

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45% of the current 862 members (I deleted 800+ inactive accounts last year) showed up ≤ five times. These are the black holes (“Feed me!”). BTW, you rank #2 when it comes to posts/day. ;-)

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

jag009
★★★

NJ,
2013-10-29 21:23
(4199 d 22:29 ago)

@ Helmut
Posting: # 11808
Views: 7,492

Rant…

Post reply

Hi Helmut,

❝ 45% of the current 862 members (I deleted 800+ inactive accounts last year) showed up ≤ five times. These are the black holes (“Feed me!”). BTW, you rank #2 when it comes to posts/day. ;-)

One of these days I will fly over so we can have a medieval sword fighting match to expel our anger. :-D

One of my formulators asked "We have a single pt dissolution (IR) and failed f₂), what should we do? My reply "Who gives a crap, my bio passed BE!"

John

Helmut
★★★

Vienna, Austria,
2013-10-29 22:09
(4199 d 21:44 ago)

@ jag009
Posting: # 11809
Views: 7,494

Rant…

Post reply

Hi John,

❝ […] we can have a medieval sword fighting match to expel our anger. :-D

❝ One of my formulators asked "We have a single pt dissolution (IR) and failed f₂), what should we do? My reply "Who gives a crap, my bio passed BE!"

Are you serious?

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

jag009 ★★★ NJ, 2013-10-30 16:03 (4199 d 03:50 ago) @ Helmut Posting: # 11819 Views: 7,348	Rant… Post reply
	Hi Helmut, ❝ Are you serious? He had a blank expression on his face so I guess it wasn't a joke. In another occasion when we had full T + R dissolution profiles and failed f₂ but passed BE (with flying color). He still asked the same question for confirmation. I love my job... John

Helmut
★★★

Vienna, Austria,
2013-10-30 16:20
(4199 d 03:32 ago)

@ jag009
Posting: # 11820
Views: 7,322

Rant…

Post reply

Hi John,

❝ He had a blank expression on his face so I guess it wasn't a joke.

Lights on, nobody at home.

❝ In another occasion when we had full T + R dissolution profiles and failed f₂ but passed BE (with flying color). He still asked the same question for confirmation.

Are you sure he doesn’t work for the Malaysian agency BPFK in his freetime?

❝ I love my job...

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

luvblooms
★★

India,
2013-10-30 08:05
(4199 d 11:47 ago)

@ jag009
Posting: # 11811
Views: 7,422

Rant…

Post reply

Hi John

❝ One of my formulators asked "We have a single pt dissolution (IR) and failed f₂), what should we do? My reply "Who gives a crap, my bio passed BE!"

I struggle with my regulatory team almost daily on this f2 topics specially where para IV are of concern (mainly where formulation strategy based patents are important and we have done something totally opposite to come out of patent).

Life is tough!!! ;-)

Regards

—
~A happy Soul~