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jag009
Hero

NJ,
2015-09-21 23:19

Posting: # 15434
Views: 8,578
 

 New D. Guid­ance – Dabigatran [Regulatives / Guidelines]

Hi folks,

Any thoughts? Guidance

John
nobody
Senior

2015-09-22 11:04

@ jag009
Posting: # 15438
Views: 7,635
 

 New D. Guid­ance – Dabigatran

Hi John!

Any info on what has changed from 2012 draft to 2015 version?

Regards

nobody

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-22 11:43

@ nobody
Posting: # 15439
Views: 7,996
 

 The FDA’s fourth BE approach!

Hi nobody,

» Any info on what has changed from 2012 draft to 2015 version?

Jun 2012
  • Design: Single-dose, two-way crossover in vivo

  • Additional Comments: Applicants may consider using a reference-scaled average bioequivalence approach for dabigatran etexilate. Please refer to Progesterone Capsules Guidance for information regarding statistical analysis method using the reference scaled average bioequivalence approach.

  • Bioequivalence based on (90% CI): free (non-conjugated) dabigatran
Sep 2015
  • Design: Single-dose, 2-treatment, 2-sequence, 4-period, fully replicated crossover in vivo

  • Additional comments: Dabigatran demonstrated a steep exposure-response relationship for both efficacy and safety. Therefore applicants should not use the reference-scaled average bioequivalence (BE) approach to widen the BE limits for dabigatran BE evaluation. Applicants should use the average BE approach, with BE limits of 80–125%. The within-subject variability of test and reference products should be compared and the upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5. For details about the Method for Statistical Analysis comparing within-subject variability of test and reference products, refer to Guidance on Warfarin Sodium.

    All subjects should have prothrombin time (PT), activated partial thromboplastin time (aPTT), and creatinine clearance (CrCl) measured. The PT and aPTT should be within the normal range and the CrCl value should be more than 50 mL/min for each subject before dosing in order to prevent or avoid the possibility of bleeding.

  • Bioequivalence based on (90% CI): free (non-conjugated) dabigatran and total dabigatran (non-con­ju­gated plus conjugated dabigatran)

Apart from the additional safety parameters for inclusion and the BE requirement of total dabigatran the statistics are interesting – going from RSABE (widening of implied limits) to sumfink similar to Warfarin. No narrowing of BE limits but still the comparison of variances.*

This gives yet a fourth BE approach stated by the FDA:
  1. Generally average BE; acceptance range 80.00–125.00%. Designs: Two-period crossover, higher-order crossovers, parallel, full (4-period) or partial replicate (3-period).
  2. RSABE for HVDs/HVDPs if swR ≥0.294. GMR-restriction 0.8000–1.2500. Designs full (4-period) or partial replicate (3-period).
  3. RSABE for NTIDs. Narrowing BE-limits based on swR. Must pass conventional ABE as well. Upper CL of swT/swR ≤2.5. Design full (4-period) replicate.
  4. As above but conventional BE limits (no downscaling).

  • How could one estimate the sample size? Yet another method for the wish-list of PowerTOST?
    You could work by trial-and-error; assessing p(BE-ABE) and p(BE-sratio):
    library(PowerTOST)
    theta0 <- 0.95      # GMR
    n      <- 16        # minimum mandated by the FDA
    CV     <- 0.2       # average (pooled) CV
    ratio  <- 1         # ratio of SEs
    CVs    <- CVp2CV(CV=CV, ratio=ratio^2)
    print(CVs)
    power.NTIDFDA(theta0=theta0, CV=CVs, n=n, design="2x2x4", details=TRUE)

    For a ratio of 1 I get p(BE-ABE)=0.95041 and p(BE-sratio)=0.95128. Fine.
    The maximum ratio for 80% power seems to be 1.25 (CVT 0.221, CVR 0.176): p(BE-ABE)=0.95041 and p(BE-sratio)=0.80843.

[image]Regards,
Helmut Schütz 
[image]

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nobody
Senior

2015-09-22 13:06

@ Helmut
Posting: # 15442
Views: 7,569
 

 The FDA’s fourth BE approach!

...nice question for statistics exam:

Please elucidate the scientific background for the "upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5" of FDA dabigatran BE guidance

:-D

Just kidding!

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-22 13:25

@ nobody
Posting: # 15443
Views: 7,590
 

 The FDA’s fourth BE approach!

Hi nobody,

» Please elucidate the scientific background for the "upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5" of FDA dabigatran BE guidance

As if pulling a rabbit out of the hat. László Endrényi regularly goes ballistic on this issue. He showed already twenty years ago (in the context of IBE) that this limit is arbitrary and the “method” flawed.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
jag009
Hero

NJ,
2015-09-23 20:29

@ Helmut
Posting: # 15461
Views: 7,203
 

 The FDA’s fourth BE approach! Yada Yada Yada

Hi Helmut,

» As if pulling a rabbit out of the hat. László Endrényi regularly goes ballistic on this issue. He showed already twenty years ago (in the context of IBE) that this limit is arbitrary and the “method” flawed.

I was in one local BA/BE meeting last week in NJ. One of the ex-FDA presenter (consultant) made a short "blasting" speech on the Sub*formulation interaction test on Concerta... I wonder when my old prof Laszlo will start his own campaign....

John
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-23 22:06

@ jag009
Posting: # 15464
Views: 7,188
 

 Yucky…

Hi John,

I like how you modified the subject line. ;-)

» I was in one local BA/BE meeting last week in NJ. One of the ex-FDA presenter (consultant) made a short "blasting" speech on the Sub*formulation interaction test on Concerta...

I see! Which kind of eternal wisdom did he segregate?

» I wonder when my old prof Laszlo will start his own campaign....

I talked to him a couple of times on this. It’s on his to-do-list…

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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d_labes
Hero

Berlin, Germany,
2015-09-22 14:08

@ Helmut
Posting: # 15447
Views: 7,543
 

 The FDA’s fourth BE approach!

Dear Helmut, dear all,

Interesting. Seems another Mighty Oracle that went into labour and delivered a mouse.

» How could one estimate the sample size? Yet another method for the wish-list of PowerTOST?

Your wish is my command!
Should not that hard to modify power.NTIDFDA() to not shrinken the acceptance range. But in the mean time I suffer from names :cool: for the functions in PowerTOST.
How should we baptize the new baby? Or better having an additional argument in the already mature power.NTIDFDA()? If yes, how to name this?

Regards,

Detlew
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-22 14:27

@ d_labes
Posting: # 15448
Views: 7,589
 

 New PowerTOST function(s)

Dear Detlew,

welcome back! How was vacation on the lonesome isle far out on the high seas?

» Interesting. Seems another Mighty Oracle that went into labour and delivered a mouse.

:-D

» » How could one estimate the sample size? Yet another method for the wish-list of PowerTOST?
»
» Should not that hard to modify power.NTIDFDA() to not shrinken the acceptance range. But in the mean time I suffer from names :cool: for the functions in PowerTOST.
» How should we baptize the new baby? Or better having an additional argument in the already mature power.NTIDFDA()? If yes, how to name this?

I would not add other argument(s) to power.NTIDFDA(). AFAIK dabigatran is actually pretty highly variable (see here: Cmax 59.9%, AUC 52.9% and the Australian PAR). BTW, if you add argu­ments you would have to change the default theta0 from 0.975 (to 0.95 or even 0.90?). Will con­fuse users. I would suggest new functions like power.RatioSFDA() and sampleN.RatioSFDA() instead. Let’s ask Ben as well.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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d_labes
Hero

Berlin, Germany,
2015-09-22 14:59

@ Helmut
Posting: # 15449
Views: 7,516
 

 New PowerTOST function(s)

Dear Helmut,

» welcome back! How was vacation on the lonesome isle far out on the high seas?

Thanks! It was very recreative. And I could practise what I have to do if I will be a rendeer (German Rentier) next time.
Doing nothing the whole blessed day but "Maulaffen feil halten" (to gawk, to sit on one's hands) :cool:.

» I would not add other argument(s) to power.NTIDFDA(). AFAIK dabigatran is not a NTID.

That astonishes me. I had interpreted the sentence "Dabigatran demonstrated a steep exposure response relationship for both efficacy and safety." as some sort of NTID.

» Let’s ask Ben as well.

Good idea. I will wait for his reaction.

BTW: Do you think this sort of BE evaluation is not an "Eintagsfliege" (nine day wonder, ephemera), specific for dabigatran?

Regards,

Detlew
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-22 15:16

@ d_labes
Posting: # 15450
Views: 7,587
 

 Pradaxa = HVDP (dabi­ga­tran = HVD?)

Dear Detlew,

» It was very recreative. And I could practise what I have to do if I will be a rendeer (German Rentier) next time.
» Doing nothing the whole blessed day but "Maulaffen feil halten" (to gawk, to sit on one's hands) :cool:.

That’s not the worst thing one can do!

» » I would not add other argument(s) to power.NTIDFDA(). AFAIK dabigatran is not a NTID.
»
» That astonishes me.

See the linked references I added in the meantime to my previous post.

» I had interpreted the sentence "Dabigatran demonstrated a steep exposure response relationship for both efficacy and safety." as some sort of NTID.

Me too. Seems that the innovator (Boehringer Ingelheim) assessed the variabilities in its studies.
This is the first example I’m aware of where the observation “HVDs/HVDPs are safe drugs since they have a flat dose/response-curve” seemingly does not hold.
Another question comes into my mind: How the heck did Boehringer’s formulation “survive” phase III and/or bridging from the formulation used in phase III to the marketed formulation?
:confused:
A dirty story? Wikipedia:

On July 26, 2014, the British Medical Journal (BMJ) published a series of investigations that accused Boehringer of withholding critical information about the need for monitoring to pro­tect patients from severe bleeding, particularly in the elderly. Review of internal com­mu­nications between Boehringer researchers and employees, the FDA and the EMA revealed that Boehringer researchers found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to with­hold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require mon­i­tor­ing.1,2


» BTW: Do you think this sort of BE evaluation is not an "Eintagsfliege" (nine day wonder, ephemera), specific for dabigatran?

No idea. Let’s ask generic companies to follow the path the innovator walked?


  1. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ. 2014;349:g4670. doi:10.1136/bmj.g4670. free download
  2. Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ. 2014;349:g4517. doi:10.1136/bmj.g4517.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Shuanghe
Regular

Spain,
2015-09-22 16:53

@ Helmut
Posting: # 15451
Views: 7,500
 

 Pradaxa = HVDP (dabi­ga­tran = HVD?)

Hi all,

» » BTW: Do you think this sort of BE evaluation is not an "Eintagsfliege" (nine day wonder, ephemera), specific for dabigatran?
»
» No idea. Let’s ask generic companies to follow the path the innovator walked?

There's another guidance of rivaroxaban which takes the same approach as dabigatran.

Unfortunately, I've done BE studies for both dabigatran and rivaroxaban and one of the dossiers have been submitted. Now I have to do some additional analysis according to the new requirements and waiting for the deficient letter to come. :-(

By the way, dabigatran is highly variable under fasting condition but not under fed condition. At least based on my 6 studies (EU/US, pilot/pivotal), all fed study showed ISCV < 30% while all fasting study showed ISCV > 40%.

As for rivaroxaban, it's high variable only for 20mg under fasting. under fed, not so much.

All the best,
Shuanghe
d_labes
Hero

Berlin, Germany,
2015-09-23 08:34

@ Shuanghe
Posting: # 15455
Views: 7,266
 

 HVNTID's

Dear Shuanghe,

» There's another guidance of rivaroxaban which takes the same approach as dabigatran.

THX for this information. So it seems it is worth the efforts to implement this BE approach in PowerTOST.

Regards,

Detlew
Shuanghe
Regular

Spain,
2015-09-25 16:14

@ d_labes
Posting: # 15469
Views: 6,709
 

 HVNTID's

Dear Detlew,

» ... So it seems it is worth the efforts to implement this BE approach in PowerTOST.

Wow! That's something worth waiting for!! :-D

All the best,
Shuanghe
d_labes
Hero

Berlin, Germany,
2015-09-23 08:23

@ Helmut
Posting: # 15454
Views: 7,484
 

 Highly variable NTID

Dear Helmut,

» » I had interpreted the sentence "Dabigatran demonstrated a steep exposure response relationship for both efficacy and safety." as some sort of NTID.
»
» Me too. Seems that the innovator (Boehringer Ingelheim) assessed the variabilities in its studies.
» This is the first example I’m aware of were the observation “HVDs/HVDPs are safe drugs since they have a flat dose/response-curve” seemingly does not hold.

Oh I see. That's the reason for the sentence "Therefore applicants should not use the reference-scaled average bioequivalence (BE) approach to widen the BE limits for dabigatran BE evaluation" in the dabigatran guidance.

Seems it's time for a new term: HVNTID :cool:

» A dirty story? Wikipedia ...

A really dirty story :vomit:. So much to "To cheat is Indian" (My exculpation to the Indian members of this forum).

Regards,

Detlew
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-23 13:20

@ d_labes
Posting: # 15460
Views: 7,294
 

 What a mess!

Dear Detlew,

» » This is the first example I’m aware of were the observation “HVDs/HVDPs are safe drugs since they have a flat dose/response-curve” seemingly does not hold.
» » A dirty story? Wikipedia ...
»
» A really dirty story :vomit:.

Indeed! On another note I don’t understand why the FDA came up with their “BE approach #4”. It would have been sufficient to state “apply the NTID-approach given in the Warfarin guidance”. With the reported CVs (@Shuanghe: Did you ever observe one <21.42%?) downscaling would be unlikely. The sample size would be driven by part of the requirement “must pass 80.00–125.00%”. Sample sizes (80% power, 4-period full rep­li­cate, CVT=CVR):

      expected GMR
 CV    0.90  0.95
0.25    32    18
0.30    40    22
0.35    54    28
0.40    68    34
0.45    84    42
0.50   102    50
0.55   120    60
0.60   140    68

However; I guess the FDA wanted to play it ”safe”. But: Given that for dabigatran no dose-titration and TDM – as for Warfarin – is (falsely?) suggested by Boehringer (despite the observed bleeding-rates!) I would classify it as a NTID and ask even for the EMA’s more strict limits of 90.00–111.11% regardless the variability. Sample sizes (80% power, GMR 0.95, CVT=CVR):

          design
 CV   2×2×2   2×2×4
0.25   258     130
0.30   366     184
0.35   492     246
0.40   630     316
0.45   782     392
0.50   946     474
0.55  1120     560
0.60  1302     652


In this post I linked to Boehringer’s ‘world record’ study. Incidentally it was dabigatran… Unfortunatelly the pranial state was not given (fasting?). Did not pass FDA’s RSABE for total dabi­ga­tran (primary) and conventional ABE for free dabi­ga­tran (secondary).
  Total dabigatran
metric  upper 95% lin. crit.   PE
AUCt     -0.082 (pass; ≤0)   1.2633 (fail; outside 0.8000–1.2500)
Cmax     -0.085 (pass)       1.2549 (fail)

No RSABE-analysis was presented for AUC; failed ABE (90% 118.32–131.51).
  Free dabigatran
metric    PE       90% CI
AUCt    126.22  119.36–133.47 (fail)
AUC∞    124.49  118.11–131.21 (fail)
Cmax    125.30  118.42–132.59 (fail)

The FDA’s 2012 guidance recommended RSABE for free dabigatran only – which was not pre­sented by Boehringer on ClinTrials.gov. Nevertheless, given the PEs of AUCt and Cmax the study would have failed to show RSABE. The highest ISCV was observed for Cmax of free dabigatran with ~48%. Were the primary and secondary targets switched by Boeh­ringer in May 2012 (from free to total dabi­ga­tran)?

My question from above
» » How did Boehringer’s formulation “survive” phase III and/or bridging from the formulation used in phase III to the marketed formulation?
still holds. :angry:

I expect that the FDA’s guidance for yet another NOAC (apixaban) will be revised as well.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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d_labes
Hero

Berlin, Germany,
2015-09-24 09:18

@ Helmut
Posting: # 15465
Views: 7,023
 

 Messy numbers - PowerTOST V1.3-01 preview

Dear Helmut,

» ... On another note I don’t understand why the FDA came up with their “BE approach #4”. It would have been sufficient to state “apply the NTID-approach given in the Warfarin guidance”. Given the reported CVs [...] downscaling would be unlikely. The sample size would be driven by part of the requirement “must pass 80.00–125.00%”. Sample sizes (80% power, 4-period full rep­li­cate, CVT=CVR):

IMHO totally correct. Lets compare NTIDFDA to HVNTID via the upcoming PowerTOSTV1.3-01 new function sampleN.HVNTID():

          GMR= 0.90       GMR= 0.95
  CV   NTIDFDA HVNTID  NTIDFDA HVNTID
 ------------------------------------
 0.20    36     20       18     14
 0.25    32     30       18     18
 ------------------------------------
 0.30    40     40       22     22
 0.35    54     54       28     28
 0.40    68     68       34     34
 0.45    84     84       42     42
 0.50   102    102       50     50
 0.55   120    120       60     60
 0.60   140    140       68     68


As expected: Identical numbers for higher variabilities, nearly totally driven by the ABE requirement :cool:.
For instance GMR=0.95, n from table above, power.NTIDFDA(..., details=TRUE)

CV       p(BE)  p(BE-sABEc)    p(BE-ABE) p(BE-sratio)
0.3    0.82570      0.95213      0.83752      0.99070
0.4    0.80727      0.99704      0.80747      0.99974
0.5    0.80496      0.99993      0.80496      1.00000
0.6    0.80286      1.00000      0.80286      1.00000
p(BE-sABEc) = prob. of scaled ABE test alone
p(BE-ABE)   = prob. of ABE test alone
p(BE-sratio)= prob. of test of variabilities alone


Of course HVNTID is simpler. No need to deal with "linearized scaled ABE criterion" and it's 95% upper CI.

Regards,

Detlew
Shuanghe
Regular

Spain,
2015-09-25 16:32

@ Helmut
Posting: # 15470
Views: 6,734
 

 What a mess!

Dear Helmut,

» ... Given the reported CVs (@Shuanghe: Did you ever observe one <21.42%?) downscaling would be unlikely.

For AUC, yes. as low as 15% under fed, but for Cmax, my lowest ISCV of R is about 24% under fed.

» I expect that the FDA’s guidance for yet another NOAC (apixaban) will be revised as well.

I'd expect it the same as those two.

All the best,
Shuanghe
Helmut
Hero
Homepage
Vienna, Austria,
2015-09-23 00:10

@ d_labes
Posting: # 15453
Views: 7,413
 

 OT: power.NTIDFDA()

Dear Detlew,

» […] the already mature power.NTIDFDA()?

Another suggestion for power.NTIDFDA(). Consider returning a list of the three ps if details=TRUE instead of

cat("p(BE-ABE)=", p["BEabe"],"; p(BE-SABEc)=", p["BEul"],
    "; p(BE-sratio)=", p["BEsratio"],"\n")
cat("\n")

inside the function. Would allow to automate stuff at the end of this post for advanced users (say, solve for a maximum ratio given a sample size, etc).

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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d_labes
Hero

Berlin, Germany,
2015-09-23 09:37

@ Helmut
Posting: # 15457
Views: 7,271
 

 OT: power.NTIDFDA()

Dear Helmut,

as already stated: Your wish is my command :-D.

Regards,

Detlew
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