Bioequivalence and Bioavailability Forum • SABE or Normal BE?

luvblooms
★★

India,
2013-02-19 06:07
(4450 d 22:57 ago)

(edited on 2013-02-19 10:20)
Posting: # 10053
Views: 13,912

SABE or Normal BE? [RSABE / ABEL]

Dear All

Recently US FDA has published a Draft Guidance on Tacrolimus Capsule bioequivalence where it has suggested following

Type of study: Fasting and Fed
Design: Single-dose, 4-way, fully replicated crossover design in-vivo
Strength: 5 mg
Subjects: Healthy males and nonpregnant females, general population.
Additional Comments: Applicants may consider using the reference-scaled average bioequivalence approach for tacrolimus.

For details about Method for Statistical Analysis Using the Reference-Scaled Average Bioequivalence Approach for narrow therapeutic index drugs,sposnors are suggested to refer to recently published draft Guidance on Warfarin Sodium.
It says that
The study should be a fully replicated crossover design in order to
• Scale bioequivalence limits to the variability of the reference product; and
• Compare test and reference product within-subject variability.
Later on I found something which left me drooling :confused:

On page 3, step 3 it was written as
Use the unscaled average bioequivalence procedure to determine BE for individual PK parameter(s). Every study should pass the scaled average bioequivalence limits and also regular unscaled bioequivalence limits of 80.00-125.00%

Now questions are

a) Now in view of these lines, does a full replicate study is really going to help any sponsor in getting widening or still need to follow 80-125?

b) Cmax and AUC of Tacrolimus are not highly variable (Cmax~20% and AUC~16% observed in one full replicate study done at our end) then what is the need of using SABE?

—
~A happy Soul~

Helmut
★★★

Vienna, Austria,
2013-02-19 12:05
(4450 d 16:59 ago)

@ luvblooms
Posting: # 10054
Views: 12,611

FDA: rSABE for NTIDs

Post reply

Dear Luv!

❝ […] I found something which left me drooling :confused:

Glycopyrronium bromide may help. ;-)

❝ a) Now in view of these lines, does a full replicate study is really going to help any sponsor in getting widening or still need to follow 80-125?

Narrowing – not widening. See this post/followings and this presentation.

—
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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jag009
★★★

NJ,
2013-02-19 16:23
(4450 d 12:41 ago)

@ luvblooms
Posting: # 10059
Views: 12,437

SABE or Normal BE?

Post reply

Hi,

❝ Recently US FDA has published a Draft Guidance on Tacrolimus Capsule bioequivalence where it has suggested following

Where do you get page 3? I only see page 2. Is your link correct or I am still sleeping here in the east coast USA? The document I read is dated "Finalized Sep 2009, Revised Dec 2012"

❝ a) Now in view of these lines, does a full replicate study is really going to help any sponsor in getting widening or still need to follow 80-125?

FDA wants you to compare the intrasubject variation between test and reference which full replicate will give. Reason is that the difference needs to be minimal since the product is a NTI. Differences as a result of inferior pharmaceutical / manufacturing quality may be dangerous when patients switch from brand to generics. Only full replicate study will give you this info. See this slides from a FDA meeting NTI BE Presentation

Back to the page 3 info which I don't see.

❝ Use the unscaled average bioequivalence procedure to determine BE for individual PK parameter(s). Every study should pass the scaled average bioequivalence limits and also regular unscaled bioequivalence limits of 80.00-125.00%

If a parameter passes ABE, it should pass SABE correct? Okay it doesn't necessary work the other way around. But in this case, since the intrasubject variability is less than 30% (as per FDA's info on the guidance), a properly powered study with an acceptable test formulation should have no issue passing both correct?

Just my 2 cents...

John

Helmut
★★★

Vienna, Austria,
2013-02-19 18:25
(4450 d 10:39 ago)

@ jag009
Posting: # 10062
Views: 12,569

Sample size?

Post reply

Hi John,

❝ ❝ Use the unscaled average bioequivalence procedure to determine BE for individual PK parameter(s). Every study should pass the scaled average bioequivalence limits and also regular unscaled bioequivalence limits of 80.00-125.00%

❝

❝ If a parameter passes ABE, it should pass SABE correct?

Not necessarily for NTIDs according to FDA’s requirement. For any CV_WR <21.42% the acceptance range will be narrower than 80–125%. In other words, the test might pass ABE but fail rSABE.

❝ Okay it doesn't necessary work the other way around. But in this case, since the intrasubject variability is less than 30% (as per FDA's info on the guidance), a properly powered study with an acceptable test formulation should have no issue passing both correct?

Define “properly powered study”. :-D

Right now we don’t have an algo estimating the sample size taking all three conditions (rSABE, ABE, equal variances) into account. For CV_WR ≥21.42% the decision is triggered by conventional ABE, for CV_WR <21.42% one might use (as an approximation!) the downscaled acceptance ranges.*

require(PowerTOST)

sigma0 <- 0.1

for(CVwr in seq(0.05, 0.25, by=0.01)){

  sigmawr <- CV2se(CVwr)

  L       <- exp(-log(1.11111)/sigma0*sigmawr)

  U       <- exp(+log(1.11111)/sigma0*sigmawr)

  if(sigmawr > 0.211792){L <- 0.8; U <-1.25} # no scaling

  n       <- as.numeric(sampleN.TOST(

             CV=CVwr, theta0=0.95, theta1=L, theta2=U,

             design="2x2x4", print=F, details=F)[7])

  cat(round(100*CVwr,2), round(100*L,2), round(100*U,2), n, "\n")

}

%CV_wr    L      U      n

 5     94.87 105.41 8426

 6     93.88 106.52  160

 7     92.90 107.64   62

 8     91.93 108.78   38

 9     90.97 109.93   28

10     90.02 111.08   22

11     89.09 112.25   20

12     88.16 113.43   18

13     87.25 114.61   16

14     86.35 115.81   14

15     85.46 117.02   14

16     84.58 118.24   14

17     83.71 119.46   12

18     82.85 120.70   12

19     82.00 121.95   12

20     81.17 123.20   12

21     80.34 124.47   12

22     80.00 125.00   12

23     80.00 125.00   12

24     80.00 125.00   14

25     80.00 125.00   14

Realistically demonstrating BE for CV <7% with T/R 0.95 is impossible. For NTIDs FDA suggested tighter limits on content which would make a smaller difference more likely. For T/R 0.975 I got:

%CV_wr    L      U     n

 5     94.87 105.41  22

 6     93.88 106.52  18

 7     92.90 107.64  14

 8     91.93 108.78  12

 9     90.97 109.93  12

10     90.02 111.08  12

11     89.09 112.25  10

…

23     80.00 125.00  10

24     80.00 125.00  12

25     80.00 125.00  12

OK, that works. For the equality of variances cross fingers.

\(\sigma_0=0.1 \;(CV \sim 10.03\%)\)
\(\theta_s=(\log{(1.11111)})^2/{\sigma_{0}}^{2}\sim 1.11006\)
\(\sigma_{wR}=\sqrt{\log{(CV{_{wR}}^{2}+1)}}\)
\([L,U]=e^{\mp \log{(1.11111)}\cdot \sigma_{wR}/\sigma_0}\)

—
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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luvblooms
★★

India,
2013-02-20 06:26
(4449 d 22:38 ago)

@ jag009
Posting: # 10074
Views: 12,232

SABE or Normal BE?

Post reply

Hi John

❝ Where do you get page 3? I only see page 2. Is your link correct or I am still sleeping here in the east coast USA? The document I read is dated "Finalized Sep 2009, Revised Dec 2012"

Looks like you need a cup of strong black coffee.
I was mentioning about page 3 of warfarin sodium guideline.

❝ FDA wants you to compare the intrasubject variation between test and reference which full replicate will give. Reason is that the difference needs to be minimal since the product is a NTI.

Just a thought, What if the variability in the reference product is higher than test? ;-)

❝ If a parameter passes ABE, it should pass SABE correct? Okay it doesn't necessary work the other way around. But in this case, since the intrasubject variability is less than 30% (as per FDA's info on the guidance), a properly powered study with an acceptable test formulation should have no issue passing both correct?

I totally agree to what helmut said

❝ For any CVWR <21.42% the acceptance range will be narrower than 80–125%. In other words, the test might pass ABE but fail rSABE.

I tried using FARTSSIE 17 to do some random calculations

Assuming Desired Power  80%   

alpha                    5%

intra-subject CV (ISV)   20.0%

Expected mT/mR Ratio     95%-105

Lower Equivalence Limit  90.0%

Upper Equivalence Limit 111.1%

sw                        0.1980422

n                       168

n-2                     166

t(1-alpha,n-2)            1.654084714

tau2                     -7.249747184

tau1                      2.502165029

Probt(2)                  0.999999988

Probt(1)                  0.198471525

1-b                       0.801528462



Required Sample Size   168

For A full replicate study

Assuming Desired Power     80%

alpha                       5%

intra-subject CV (ISV)     20%

Expected mT/mR Ratio (%)   95%-105

Lower Equivalence Limit    90.00%

Upper Equivalence Limit   111.00%

k (= sb2 / sw2)             1

sWR                         0.1980422

n                         168

n-2                       166

t(1-alpha,n-2)              1.654084714

tau2                       -7.203445249

tau1                        2.502165029

Probt(2)                    0.999999984

Probt(1)                    0.198471525

1-b                         0.801528458

   

Required Sample Size   84

Also remember
a) higher blood loss
b) higher drop outs
c) prolonged study durations ( 3 wash out periods of 21 days)

—
~A happy Soul~

jag009
★★★

NJ,
2013-02-20 16:20
(4449 d 12:44 ago)

@ luvblooms
Posting: # 10079
Views: 12,244

SABE or Normal BE?

Post reply

Hi Luvbloom

❝ Looks like you need a cup of strong black coffee.

❝ I was mentioning about page 3 of warfarin sodium guideline.

Yeah was drinking Dunkin Donut coffee and not my fav Starbuck espresso (Still not good stuff but comparatively better) :-D

❝ ❝ FDA wants you to compare the intrasubject variation between test and reference which full replicate will give. Reason is that the difference needs to be minimal since the product is a NTI.

❝

❝ Just a thought, What if the variability in the reference product is higher than test? ;-)

Wouldn't that be wonderful then? I don't think the agency will care, or give you a medal for that. They just want to make sure that your product is not worst :-D

John

Helmut
★★★

Vienna, Austria,
2013-02-20 16:45
(4449 d 12:19 ago)

@ luvblooms
Posting: # 10080
Views: 12,316

SABE or Normal BE?

Post reply

Hi Luv,

sorry for cutting in.

❝ ❝ FDA wants you to compare the intrasubject variation between test and reference which full replicate will give. […]

❝

❝ Just a thought, What if the variability in the reference product is higher than test? ;-)

Wouldn’t matter since variabilities are compared by a one-sided test. In other words, the variability of the test must not be significantly larger than the one of the reference. Smaller is fine.

❝ I tried using FARTSSIE 17 to do some random calculations

❝

❝ Lower Equivalence Limit 90.0%

❝ Upper Equivalence Limit 111.1%

❝ …

❝ Required Sample Size 168

Nope. For CV_WR 20% (σ_WR 0.1980422) limits are upscaled from 0.9/1.11111 to 0.8116742/1.232021. Then FARTSSIE agrees with PowerTOST.

PowerTOST

sampleN.TOST(CV=0.2,theta0=0.95, theta1=0.8116742, theta2=1.232021, design="2x2x2")

+++++++++++ Equivalence test - TOST +++++++++++

            Sample size estimation

-----------------------------------------------

Study design:  2x2 crossover

log-transformed data (multiplicative model)



alpha = 0.05, target power = 0.8

BE margins        = 0.8116742 ... 1.232021

Null (true) ratio = 0.95,  CV = 0.2



Sample size (total)

 n     power

22   0.810558

FARTSSIE

Expected µT/µR Ratio     95%-105.3%

Lower Equivalence Limit  81.16742%

Upper Equivalence Limit 123.2021%

sw                        0.1980422

n                        22

n-2                      20

t(1-alpha,n-2)            1.724718004

tau2                     -4.353385162

tau1                      2.635367015

Probt(2)                  0.994693186

Probt(1)                  0.184134808

1-b                       0.810558378



Required Sample Size     22

But: For the FDA a full replicate design is mandatory anyway. Of course you are right for EMA where for some NTIDs (tacrolimus: AUC, ciclosporine: AUC and C_max) the acceptance range is fixed to 90.00–111.11%.

❝ For A full replicate study […]

I wouldn’t use FARTSIE for replicate designs any more because the sample size is estimated for a 2×2×2 design and afterwards set to 50% for full replicates and 75% for three-period designs. That’s just approximatively correct.

—
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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ElMaestro
★★★

Denmark,
2013-02-20 17:08
(4449 d 11:56 ago)

@ Helmut
Posting: # 10081
Views: 12,194

SABE or Normal BE?

Post reply

Hi Helmut, Luvblooms and others,

❝ ❝ Just a thought, What if the variability in the reference product is higher than test? ;-)

❝

❝ Wouldn’t matter since variabilities are compared by a one-sided test. In other words, the variability of the test must not be significantly larger than the one of the reference. Smaller is fine.

I think it is actually quite common to see the ref-variability exceeding that of the test. While I am no CMC expert I think the originator company's production lines are often 20+ years old, while the generic company's production lines are new. And hence tablet-to-tablet variation is oftentimes better controlled by the generic company and this accounts to some degree for the observed difference in intra-subject CV's.
Food for thought for those who blindly keep repeating their mantras that generics are just always worse than their innovator counterparts. Oddly enough there's an high percentage of these peope in innovator companies :-D

—
Pass or fail!
ElMaestro

jag009
★★★

NJ,
2013-02-21 18:10
(4448 d 10:54 ago)

@ ElMaestro
Posting: # 10093
Views: 12,060

SABE or Normal BE?

Post reply

Hi guys,

❝ I think it is actually quite common to see the ref-variability exceeding that of the test. While I am no CMC expert I think the originator company's production lines are often 20+ years old, while the generic company's production lines are new. And hence tablet-to-tablet variation is oftentimes better controlled by the generic company and this accounts to some degree for the observed difference in intra-subject CV's.

Just curious (or lazy). Has FDA ever published (or presented) data of withinsubject CV from test and reference from submitted full replicate studies?

John

Helmut
★★★

Vienna, Austria,
2013-02-21 18:18
(4448 d 10:46 ago)

@ jag009
Posting: # 10094
Views: 12,365

FDA’s example data sets

Post reply

Hi John,

❝ Has FDA ever published (or presented) data of withinsubject CV from test and reference from submitted full replicate studies?

Yes. I’m too lazy to search as well. Maybe I dig out the link later on.* It was in the good (?) ol’ days when FDA was interested in subject-by-formulation interaction and requested replicate studies. The data sets are somewhere at FDA’s site in TXT-format. No CVs, so you have to run the analyses yourself. Only the classes of drugs are given.

http://www.fda.gov/Drugs/ScienceResearch/ucm301277.htm

B. The following data show that the test formulation has a higher intrasubject variability than the reference formulation (s_WT /s_WR ratio > 1.5)
AUC: Drugs # 15a, 15b, 15c, 15e
Cmax: Drugs # 15a, 15c, 15e, 15f, 16e, 16f

C. The following data show that the test formulation has a lower intrasubject variability than the reference formulation (s_WT /s_WR ratio < 0.667)
AUC: Drugs # 1, 5, 7
Cmax: Drugs # 1, 7, 14c, 14d

Too bad that data sets 14, 15, 16 are not online…

BTW, following [msg]this thread[/msg] about data exclusion:
Drug 1: AUC_t (n=156), AUC_∞ (n=155)
Drug 2: AUC_t (n=98), AUC_∞ (n=92)
Drug 3a: AUC_t (n=140), AUC_∞ (n=138)

—
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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jag009 ★★★ NJ, 2013-02-21 21:14 (4448 d 07:50 ago) @ Helmut Posting: # 10098 Views: 12,586	FDA’s example data sets Post reply
	Hi Helmut, ❝ Too bad that data sets 14, 15, 16 are not online… I went to that link. datasets (Sub, per, trt, AUC, Cmax) for the above are online... John

Helmut
★★★

Vienna, Austria,
2013-02-21 23:42
(4448 d 05:22 ago)

@ jag009
Posting: # 10100
Views: 12,122

FDA’s example data sets

Post reply

Hi John,

❝ I went to that link. datasets (Sub, per, trt, AUC, Cmax) for the above are online...

THX! I overlooked the one-letter links in brackets. Do you believe column 7 of Drugs 15F & 16F is really C_max? Smells of t_max. :-D

—
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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jag009
★★★

NJ,
2013-02-22 16:46
(4447 d 12:18 ago)

@ Helmut
Posting: # 10108
Views: 12,262

FDA’s example data sets

Post reply

Hi Helmut,

❝ THX! I overlooked the one-letter links in brackets. Do you believe column 7 of Drugs 15F & 16F is really C_max? Smells of t_max. :-D

The datasets look kinda like .... AUC, Cmax, Tmax. I don't think the last 3 columns are AUCINF AUC CMAX unless the extrapolation was huge for AUCinf calculation... Someone was drinking vodka when they keyed the data in? Or Whiskey? :party:

John

P.S. How's the snow in your area? I am itching to fly out to go skiing in Euro soon...

Helmut
★★★

Vienna, Austria,
2013-02-22 17:33
(4447 d 11:31 ago)

@ jag009
Posting: # 10109
Views: 12,756

FDA’s example data sets

Post reply

Hi John,

❝ The datasets look kinda like .... AUC, Cmax, Tmax.

Exactly.

❝ P.S. How's the snow in your area? I am itching to fly out to go skiing in Euro soon...

Snowing in Vienna for the last 24 hours. Lots of snow everywhere in the Alps. See here (in German).

—
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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