Bioequivalence and Bioavailability Forum • Mexico BE

nobody
nothing

2014-10-15 17:38
(3804 d 15:28 ago)

Posting: # 13715
Views: 9,879

Mexico BE – add-on design? [Regulatives / Guidelines]

Hi again!

There is a BE-guidance for Mexico dated 2013

http://www.dof.gob.mx/nota_detalle_popup.php?codigo=5314833

...apparently only in Spanish.

It states under 8.5.3 that, if no bioequivalence has been shown in the study and power is <80% an "add-on" study with additional subjects can be performed, number of individuals to be added should be calculated based on the intraindividual CV (is what I would translate).

Isn't that a "follow-up"-two-stage design or did I get something wrong here? Under 8.5.1.1 it states that type I error must be below 5%?!?,.%%66#**?

—
Kindest regards, nobody

Helmut
★★★

Vienna, Austria,
2014-10-15 17:50
(3804 d 15:16 ago)

@ nobody
Posting: # 13716
Views: 8,751

Mexico BE – add-on design?

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Ὀδυσσεύς

❝ Isn't that a "follow-up"-two-stage design or did I get something wrong here? Under 8.5.1.1 it states that type I error must be below 5%?!?,

That’s wacky. A combination of the old Canadian guidance with the current Japanese + decision based on power?

❝ .%%66#**?

Perfect description. See this thread and start to simulate.

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Helmut Schütz

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nobody nothing 2014-10-15 18:47 (3804 d 14:18 ago) @ Helmut Posting: # 13717 Views: 8,598	Mexico BE – add-on design? Post reply
	I would not go that way, looks like a classical lose-lose situation to me... But maybe someone should start something of a controlled correspondence with the colleagues in Mexico to see what they accept under this regulation. Unfortunately my Spanish is ...lousy, eeehmm... cough absent... Οὐδείς — Kindest regards, nobody

Helmut
★★★

Vienna, Austria,
2014-10-15 19:38
(3804 d 13:27 ago)

@ nobody
Posting: # 13718
Views: 8,860

Rant

Post reply

<rant>

Slowly I’m getting sick of regulators introducing “methods” out of the blue (based on gut-feeling or what?) and leave it to us exploring whether these “recommendations” work at all. My private collection:

The Japanese Add-On design which inflates the patient’s risk as shown by Wonnemann et al. (2014).¹
The fixed effect sequence(stage) in EMA’s Q&A Rev.7. As shown by Karalis and Macheras (2013)² this modification is not relevant (as expected). So why was it introduced in the first place?
Some European regulators stating “Adapting the confidence intervals based upon power is not acceptable […] Confidence intervals should be selected a priori, without evaluation of the power” or even “Potvin is not valid in Europe”.
The Group Sequential Design as stated in by Health Canada’s TPD (Section 2.3.2.1). Pocock’s 0.0294 is recommended, but we read also:
“The first stage N₁ is generally based on the most likely intra-subject variance estimate with some added subjects to protect against drop-outs. The additional subjects required for the second stage N₂ is usually based on a worst-case scenario using a larger intrasubject variance estimate, such that N₁ plus N₂ is equal to the estimated sample size for the larger intra-subject variance. Usually the strategy with this design is to accept bioequivalence at the first stage and only go to the second stage when the intra-subject variance from the first stage is very large.”
Did Eric Ormsby perform simulations? From some preliminary ones I got the impression that inflation is not an issue,* but power might be extremely high if proceeding to the second stage due to a slightly larger than expected CV. Forced BE?

* Edit: Not correct and there is yet another problem. One has to assume a “worst-case” CV in order to calculate N₂ (rule of thumb: 50% higher CV ~doubles the sample size). In many cases N₁ will not be (N₁+N₂)/2 and Pocock’s 0.0294 might lead to inflation.³
Example: “Most likely” CV 15%, T/R 0.95, 80% power, expected drop-out rate 5% ⇒ N₁ 16. “Worst case” CV 30% ⇒ N₂ 28. Actual study: N₁ 15, N₂ 27
CV% alpha % power % studies % power stage 1 in stage 2 overall ─────────────────────────────────────── 15 0.05167 84.86 15.14 99.95 ‘neglible infl.’ (<0.052), sign. >0.05 21 0.05166 51.62 48.38 96.86 ‘neglible infl.’ (<0.052), sign. >0.05 30 0.04527 12.95 87.05 76.94
In other words Mr Pocock’s α doesn’t work that well. Although we tried to compensate for drop-outs, in the worst case scenario power <80%.
“[…] only go to the second stage when the intra-subject variance […] is very large.” Ahem; what is “very large”?
Indonesian regulators mandating a second stage even if a study passed already in stage 1. For details see Fuglsang (2014).⁴
… and now the descendants of Pancho Villa!

</rant>

Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 31 (preprint published 18 July 2014). doi 10.1007/s11095-014-1450-z
Karalis V, Macheras P. On the statistical model of the two-stage designs in bioequivalence assessment. J Pharm Pharmacol. 2014;66(1):48–52. doi 10.1111/jphp.12164
Jennison C, Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. Boca Raton: Chapman & Hall/CRC; 1999. p. 71–6.
Fuglsang A. A Sequential Bioequivalence Design with a Potential Ethical Advantage.
AAPS J. 2014;16(4):843–6. doi 10.1208/s12248-014-9622-7

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

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nobody
nothing

2014-10-15 20:26
(3804 d 12:40 ago)

@ Helmut
Posting: # 13719
Views: 8,582

Rant

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In my opinion these guideline things are highly political, make an educated guess how many of the guys involved know what alpha is, beware of an alpha inflation.

And then in the final round of drafting some industry-politics-lobby guys come in: "Unfair! we need a second chance, if we fail just by...ehhh... ~~being to dull to calculate the sample size~~ chance, we want an add-on!"

...and suddenly you end up with such home-bake stuff. It's the same on all levels, from small town politics to "we save the Euro" nonsense.

Time to leave office and have little fresh air! :-D

—
Kindest regards, nobody

nobody nothing 2014-10-16 12:22 (3803 d 20:44 ago) @ nobody Posting: # 13723 Views: 8,573	Mexico BE – add-on design? Post reply
	PS: If you have low blood pressure these days you might start serching for the "modified release guideline" mentioned under 8.4.16.3... Good luck! Οὐδείς — Kindest regards, nobody

Risherd
☆

Mexico,
2014-10-24 02:26
(3796 d 06:40 ago)

@ nobody
Posting: # 13792
Views: 8,437

Mexico BE – add-on design?

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Dear nobody,

I'm from Mexico and like you I'm still searching for that...

❝ "modified release guideline" mentioned under 8.4.16.3... Good luck! :ok:

Regarding the bioequivalence legislation in my country for me is kind of disappointing, we have to wait almost 15 years (15 years!) to update the only guidance that exists in this country of BE studies to got (IMHO) a bad copy of other guidances mainly both in the statistical part.

And like Helmut says our mexican guidance has a "wacky" statistical approach on bioequivalence trials, mainly because there is a mix of add-on with two-stage design :confused:

.

There is other point on this guidance that I like to share with you and I would like to know your point of view:

On the 9.6.7. indicate "The power of the study should be reported, which will be only of informative character when the conclusion of the study is bioequivalence between the drug products". That, for me ,is "No matter what power do you got on your study, if the confidence interval of your study it's between 80 - 125% the drug products are bioequivalent" :lookaround:

I'm not an expert on bioequivalence statistics but for me not taking in consideration the statistical power of the study even when the 90CI% complaint with 80-125% put a serious question of the therapeutic effectiveness of the drug products that will be avaliable on the market.

Finally, our mexican guidance it is available only in Spanish and it is a "must do legislation" not a guidance if you don't do what it says you are in serious troubles with everybody :-D

.

Regards,
Risherd.

Helmut
★★★

Vienna, Austria,
2014-10-24 02:59
(3796 d 06:07 ago)

@ Risherd
Posting: # 13793
Views: 8,386

Mexico BE – add-on design?

Post reply

¡Hola Risherd!

❝ Regarding the bioequivalence legislation in my country for me is kind of disappointing, we have to wait almost 15 years (15 years!) to update the only guidance that exists in this country of BE studies […]

Well, others don’t perform much better.
FDA: 1992 → 2003 → 2013 (draft; nobody knows when it will be finalized)
EMA: 1992 → 2001 → 2010 (a little bit quicker)

❝ On the 9.6.7. indicate "The power of the study should be reported, which will be only of informative character when the conclusion of the study is bioequivalence between the drug products".

That’s good. I like this statement. Really!

❝ That, for me ,is "No matter what power do you got on your study, if the confidence interval of your study it's between 80 - 125% the drug products are bioequivalent" :lookaround: […] but for me not taking in consideration the statistical power of the study even when the 90CI% complaint with 80-125% put a serious question of the therapeutic effectiveness of the drug products that will be avaliable on the market.

No; although this is a common misconception. Power is only related to the producer’s risk. Let’t say you planned the study for 80% power (= 20% risk of failure). The study passes BE, but ‘power’ is just 60%. You were lucky, but you made it. No, the risk is not 40%. You succeeded (to 100%, if you like).
The patient’s risk is still 5%.

❝ Finally, our mexican guidance it is available only in Spanish and it is a "must do legislation" not a guidance if you don't do what it says you are in serious troubles with everybody :-D .

It’s a brilliant idea to give technical details in a law. In the first Brazilian regulation the definition of bioavailability was wrong and it took them five years to change a single sentence.

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

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nobody
nothing

2014-10-24 10:46
(3795 d 22:20 ago)

@ Risherd
Posting: # 13794
Views: 8,373

Mexico BE – add-on design?

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Hi Risherd!

Nice to meet you, even if it's only on the virtual level!

Good to know that I'm not alone searching for the modified release guidance.

Even better to know that the guidance is a law (must be a law, I guess, otherwise no way to demand performing BE trials inside Mexico), I had some guys wanting to change the model for ANOVA, gives me even more arguments for sticking to the approach given in the guideline. :-D

In general the Mexican guidance is straight forward regarding various topics, but this add-on gives me some headaches. Do you have any experience on that? Does it have to be proposed in the initial protocol? Guess: yes, otherwise no way to preserve the consumer risk. Which statistics are accepted to keep the consumers risk at 5%?

Would be very interesting to know!

Best regards (rain, 9°C, brrrrr...)

nobody

—
Kindest regards, nobody

Helmut
★★★

Vienna, Austria,
2014-10-24 21:05
(3795 d 12:00 ago)

@ nobody
Posting: # 13803
Views: 8,445

Mexico BE – add-on design?

Post reply

Ὀδυσσεύς

I the meantime I found a PDF.

❝ […] this add-on gives me some headaches. […] Does it have to be proposed in the initial protocol? Guess: yes, otherwise no way to preserve the consumer risk.

I think so. At least in 8.5.1.1 we read about sample size planning:

“[…] el error tipo I debe ser menor o igual al 5%.”

Correct. Even if we test at a nominal α 0.05, the actual risk might be <0.05. TOST is conservative, especially for CVs >20–30% (and is to a minor degree dependent on the sample size) – see this plot. This conservatism explains the curves in the other thread. Below an updated version with identical TIE-scales of the approaches;
A unadjusted, B Bonferroni:

[image]

Dotted line: 0.05, dashed line: asymptotic maximum inflation for the chosen n₂-approach, solid line: maximum inflation.

Lower inflation for higher CVs.
Lower inflation with smaller total sample sizes.

In others words: Even if you don’t adjust, theoretically the type I error might not reach 5%. The Mexican requirement allowing to continue a study based on power <80% should add some conservatism. Practically this “works” only for HVDPs and sample sizes which’s power you wouldn’t like (i.e., forget this idea). As soon as you add enough subjects for a reasonable total sample size, you are history.
Example: You assume a CV of 30% and plan the study with 40 subjects. It turns out that the CV is 40%. “Power” is 55% (may pass by luck; let’s assume you fail). You perform the second stage with 26 subjects. If you don’t adjust, the patient’s risk will be ~7.7%. :stop:

OK; we have to comply with 8.5.1.1. It simply doesn’t work to keep 0.05 in the first stage. さようなら

❝ Which statistics are accepted to keep the consumers risk at 5%?

If you want to be on the safe side, follow Signore Bonferroni. Copy these equations to the protocol. The sample size penalty (to pass already in the first stage) is moderate (T/R 0.95, 80% power, α 0.05/0.025):


CV%   n_0.05  n_0.025

──────────────────────

15    12     16 (+33%)

20    20     24 (+20%)

25    28     36 (+29%)

30    40     50 (+25%)

40    66     82 (+24%)

50    98    124 (+27%)

Since for Mexico we need an intermediate power estimation (which could stop studies in the first stage), I guess it should be possible to use an α >0.025. Simulations required; talk to a competent statistician.
Note: Nothing is said both in the Japanese and Mexican guidance/regulation about the sample size estimation of the second stage. It seems that full adjustment (i.e., based on both the CV and T/R-ratio) is possible.

Might screw up power if you use a futility criterion.
Might lead to extreme sample sizes if you don’t.

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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

xtianbadillo ☆ Mexico, 2016-04-07 20:54 (3264 d 12:12 ago) @ nobody Posting: # 16173 Views: 6,802	Mexico BE – add-on design? Post reply
	Hello all. On January 20, 2016. The guideline for modified release was published. The same for narrow therapeutic index. http://www.cofepris.gob.mx/AS/Documents/RegistroSanitarioMedicamentos/Guias/Gu%C3%ADas%20de%20Intercambiabilidad%20de%20Medicamentos%20Gen%C3%A9ricos.pdf

Mahesh M ★ India, 2016-04-11 11:42 (3260 d 21:24 ago) @ xtianbadillo Posting: # 16180 Views: 6,440	Mexico BE – add-on design? Post reply
	Hi, xtianbadillo, Thank you so much for sharing this information. Do you have link regarding English translated version for the same. Regards

Helmut
★★★

Vienna, Austria,
2016-04-11 15:29
(3260 d 17:37 ago)

@ Mahesh M
Posting: # 16184
Views: 6,435

No English translation

Post reply

Hi Mahesh,

❝ Do you have link regarding English translated version for the same.

There is none. With 400+ million native speakers Spanish is a world language and one of the official languages of the UN. 99.3% of the Mexican population speak Spanish. Chances that the Secretaría de Salud will ever publish an English translation are close to nil. Find a certified translator.

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

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