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ioanam
Regular

Romania,
2010-06-07 13:52

Posting: # 5452
Views: 6,570
 

 NTIDs with high variability [Design Issues]

Which is the most appropriate design for a narrow therapeutic index drug with very high intra-subject variability?

For example, we have an immunosuppressive agent with an intra-subject CV% > 45%.
Using a standard two – way crossover design with acceptance interval tightened (90.00 – 111.11%), we will have a sample size of more than 300 subjects :-(.

It is possible to use a replicate design in this situation?

Thank you,
Jo
Helmut
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Vienna, Austria,
2010-06-07 14:18

@ ioanam
Posting: # 5453
Views: 5,945
 

 NTIDs # HVDs (or not?)

Dear Jo!

» Which is the most appropriate design for a narrow therapeutic index drug with very high intra-subject variability?

This is strange. NTIDs are generally not highly variable – otherwise they wouldn’t have ‘survived’ the MA in the first place.

» For example, we have an immunosuppressive agent with an intra-subject CV% > 45%.

Oops?! Can you give us the name of the drug?

» Using a standard two – way crossover design with acceptance interval tightened (90.00 – 111.11%), we will have a sample size of more than 300 subjects :-(.

Well…

» It is possible to use a replicate design in this situation?

If we are talking about immunosuppressants, we are talking about a study in patients, right? Steady state too. Likely parallel design – it’s unethical to interrupt treatment by a washout. The disease state may change between periods which will prevent a cross-over anyhow.
Even if you opt for a cross-over, a replicate design doesn’t help in the reducing the numbers of treat­ments applied (or in other words, the number of biosamples and study costs). If the 2×2 study size is 300, the size for a 4-period replicate is still 150, but expect more drop-outs and problems with the increased number of blood samples / subject.

Cheers,
Helmut Schütz
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ioanam
Regular

Romania,
2010-06-07 18:17

@ Helmut
Posting: # 5458
Views: 5,925
 

 NTIDs # HVDs (or not?)

Dear Helmut
Thank you for your response.

I am talking about sirolimus. This agent have a high intra-subject CV%, but is also subject for TDM.

"The therapeutic window of sirolimus may be relatively narrow. Therefore, optimal use of sirolimus requires careful attention to maintenance of therapeutic levels". (National PBM Drug Monograph Sirolimus (Rapamune®)).
and
"As described for the solution, the intra- and inter-individual variability in trough levels is high (40-50%)" (see page 17 in the following link http://www.ema.europa.eu/humandocs/PDFs/EPAR/rapamune/420600en6.pdf).

The problem here is that the sponsor requested a bioequivalence study in healthy subjects.
I have seen before different studies performed with other immunosuppressives (cyclosporin) in healthy volunteers, but only 2-way crossover. Any increase number of periods will harm the safety profile. :-(

I don't know what to do now. Too many subjects to be enrolled.
Kindest regards, Jo


Edit: Document linked. [Helmut]
ElMaestro
Hero

Denmark,
2010-06-07 18:28

@ ioanam
Posting: # 5459
Views: 5,893
 

 Complicated

Dear ioanam,

This is a tricky situation. I would encourage you to (ask the man with the money to) seek scientific advise or whatever equivalent is available if your target market is not Europe. You have a complicated drug, complicated info on the ref SPC, and you need to tiptoe through an ethical mine field.

I agree with HS, that a parallel study in patients is likely to be the way to do it.

Best regards
EM.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Dr_Dan
Senior

2010-06-08 12:24

@ Helmut
Posting: # 5468
Views: 5,831
 

 NTIDs # HVDs (or not?)

Hi Helmut

» If we are talking about immunosuppressants, we are talking about a study in patients, right? Steady state too. Likely parallel design – it’s unethical to interrupt treatment by a washout.

If you investigate steady state PK you can do an "active washout" without interrupting treatment.

Regards
Dan

Kind regards and have a nice day
Dr_Dan
Helmut
Hero
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Homepage
Vienna, Austria,
2010-06-08 12:34

@ Dr_Dan
Posting: # 5469
Views: 5,925
 

 Switch over

Dear Dan!

» If you investigate steady state PK you can do an "active washout" without interrupting treatment.
Oops, got me! You are absolutely right. :clap:
My concerns about stable conditions in patients preventing a cross-over still remain.

Cheers,
Helmut Schütz
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Relaxation
Junior

Germany,
2010-06-09 22:38
(edited by Relaxation on 2010-06-10 16:22)

@ Helmut
Posting: # 5488
Views: 5,920
 

 NTIDs # HVDs (or not?)

Hello everybody and a nice evening.

From my point of view and experience, the discussion on narrow therapeutic drugs seems to be becoming more and more important. However, I just wanted to point on one issue. Actually, I just registered for this; always wanted but needed a little push.

The problem for the greater part evolves from

» "As described for the solution, the intra- and inter-individual variability in trough levels is high (40-50%)"

, doesn't it. But trough values (roughly Cmin) not only might show higher variability in general but, at least in Europe, are not a parameter in BE assessment for IR formulations.
Don't hesitate to correct me here, maybe I missed just something important?
Based on this I would recommend to reconsider the basis of the sample size estimation (back to literature).

With best regards,

Relaxation.

Edit: Okay, I screwed it up. Any chance someone might move this to the end of the thread :waving:.


Edit: Welcome to the club! I think you posted in the right place, because you replied to and quoted Jo's post. If you still want, I can link the post to mine. Simply reply with yes/no. BTW, you are absolutely right about Cmin for IR formulations. [Helmut]

Edit: Thanks for the welcome. Yes, I would prefer a placement closer to the end. Might have to get used to the wiki-style-"post to the post", though.
Thanks a lot.

Edit: Moved. [Helmut]
krishna
Junior

India,
2013-01-07 14:01

@ Relaxation
Posting: # 9795
Views: 4,925
 

 FDA scaling for NTIDs

Hi to all,

» » "As described for the solution, the intra- and inter-individual variability in trough levels is high (40-50%)"

As per the recent guideline of FDA for warfarin sodium Tablets, they designed the BE acceptance criteria assuming all NTIs are low variable. I have gone thorough the guideline it is very stringent to rest of regulatory.

I want to discuss the guideline here. With no constraint on the point estimate, suggested SABE(sigm0=0.1 and delta=1.11), ABE and upper 90% CL of sigmT/sigmR <=2.5. Suppose if the full replicated study results are like for Cmax: 86.00 (80.00 - 93.00) with %CV: 26, then the study passing with SABE, also with ABE and test variability is less than the Refe variability. Even, in the guideline they didn't mention about cut off for maximum sigmaR. So, what is the advantage of above stringent criteria in this case? Correct me if i am wrongly interpreted?

Thanks,
Krishna


Edit: Guidance linked and subject line changed. [Helmut]
Helmut
Hero
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Vienna, Austria,
2013-01-12 20:06

@ krishna
Posting: # 9833
Views: 4,856
 

 FDA scaling for NTIDs

Hi Krishna,

» As per the recent guideline of FDA for warfarin sodium Tablets, they designed the BE acceptance criteria assuming all NTIs are low variable.

Likely they are. From a presentation by Lawrence Yu:1

Residual variability (%CV) from ANDAs reviewed between 1996–2008
                              AUC0-t             Cmax
Drugs                    Mean     Range     Mean     Range
Warfarin (n=29)           5.7   3.3, 11.0   12.7   7.7, 20.1
Levothyroxine (n=9)       9.3   3.8, 15.5    9.6   5.2, 18.6
Carbamazepine (n=15)      8.0   4.4, 19.4    8.7   5.2, 17.6
Lithium Carbonate (n=16)  7.8   4.5, 14.0   13.5   6.4, 24.4
Digoxin (n=5)            21.7  13.1, 32.2   21.0  14.3, 26.1
Phenytoin (n=12)          9.2   4.1, 18.6   14.9   7.4, 20.0
Theophylline (n=3)       17.9  12.8, 24.2   18.2  11.8, 25.8


» I have gone thorough the guideline it is very stringent to rest of regulatory.

Agree. I think it is an attempt to avoid arbitrary limits ignoring potential differences in variances – important if formulations are switched under treatment. Reminds me somehow on IPE/PBE of the late 1980s.

» […] Suppose if the full replicated study results are like for Cmax: 86.00 (80.00 - 93.00) with %CV: 26

Hhm, √0.80 × 0.93 0.86. ;-) If I interpret your example right the study was a full replicate in 32 subjects.

» […] then the study passing with SABE, also with ABE and test variability is less than the Refe variability.

The study passes all criteria. What is the problem?

» Even, in the guideline they didn't mention about cut off for maximum sigmaR.

[image]

Scaling may result in an acceptance range wider than the conventional one2 (if CVWR >21.42%; scaled limits for your 26% would be 76.38–130.93%). Ways out:
  1. A cutoff on sWR (the estimate of σWR) and switch to conventional unscaled ABE. Donald Schuirmann explored values of 0.21179 (CV 21.42%) and 0.21 (CV 21.23%).
  2. A “Must Pass Both” criterion: RSABE + ABE
Both methods preserve the patient’s risk with the same power. Empiric α was lower (more conservative) with method #2. I guess that’s the reason FDA implemented this method in their guidance.

» So, what is the advantage of above stringent criteria in this case?

The replicate design allows comparison of σWT with σWR. Arbitrary narrowing the AR does not take the actual variance into account.
Not an advantage but an obstacle: sample size estimation. Simulations are required and IMHO a pilot study is unavoidable.


  1. Yu LX. Approaches to Demonstrate Bioequivalence of Critical Dose Drugs
    Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 13 April, 2010.
    online
  2. Schuirmann DJ. Evaluation of Scaling Approaches to Demonstrate BE of NTI Drugs – OGD Simulation Efforts
    Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 26 July, 2011.
    online


P.S.: Nice to know:
  • Simulations were carried out in the S-Plus, R [sic], or APL computer programming languages
  • Each estimated probability based on one million (1,000,000) simulated studies

Cheers,
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. ☼
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krishna
Junior

India,
2013-01-18 10:04

@ Helmut
Posting: # 9889
Views: 4,515
 

 FDA scaling for NTIDs

Hi Helmut,

Thanks for your reply.

» Hhm, √0.80 × 0.93 0.86. ;-) If I interpret your example right the study was a full replicate in 32 subjects.

It is 86.25.

» The study passes all criteria. What is the problem?

My problem is, here %(T/R): 86.25, it is far way from the 100 and R-R %CV: 26. Due to higher CV it is passing SABE (it would have been failed in SABE if it had low variability). Then how test can be assured with therapeutic equivalence as Reference with out point estimate constraint ?

Thanks,

Krishna.
Helmut
Hero
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Homepage
Vienna, Austria,
2013-01-20 12:46

@ krishna
Posting: # 9893
Views: 4,596
 

 FDA scaling for NTIDs

Hi Krishna,

» » The study passes all criteria. What is the problem?
»
» My problem is, here %(T/R): 86.25, it is far way from the 100 and R-R %CV: 26. Due to higher CV it is passing SABE (it would have been failed in SABE if it had low variability). Then how test can be assured with therapeutic equivalence as Reference with out point estimate constraint ?

We are talking about the FDA. Until recently FDA did not distinguish between NTIDs and other drugs at all. The acceptance range was 80.00–125.00%, no PE restriction. So the study would have passed anyway. If you read the transcripts of the 2010 and 2011 ACPSCP-meetings you will realize the rationale behind the new method is last but not least political (as is the PE restriction for HVDPs). With the aggregate method ≤21.42 %CV the RSABE will mainly be responsible for the decision and >21.42 conventional ABE. This makes sense, since if a NTID is safe and efficacious despite such a variability there is no reason to impose a restriction. Furthermore as Donald Schuirmann showed in his simulations the patient’s risk has a minimum of ~0.025 at 21.42 %CV.

Cheers,
Helmut Schütz
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krishna
Junior

India,
2013-02-01 12:20

@ Helmut
Posting: # 9941
Views: 4,371
 

 FDA scaling for NTIDs

Dear Helmut,

Many thanks for your explanation. I got the point.

Regards,
Krishna.
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