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Back to the forum  Query: 2017-03-23 09:20 CET (UTC+1h)
 
jag009
Hero

NJ,
2017-03-20 04:42
(edited by jag009 on 2017-03-20 05:22)

Posting: # 17166
Views: 284
 

 Highly Variable Drug BE Justification [Regulatives / Guidelines]

Hi all,

Just want to know what your experience is on this matter.

The FDA stated that "Special Considerations: Applicants may consider using a reference-scaled average bioequivalence approach for x drug. If using this approach, the applicant should provide evidence of high variability (i.e., within-subject variability ≥30%) in bioequivalence parameters. Applicants who would like to use this approach are encouraged to submit a protocol for review by the Division of Bioequivalence in the Office of Generic Drugs."

The above implies that one can conduct replicate studies (RSABE) if he/she has supportive data (ISCV>=30%). What if one conducted pilot studies and found that the ISCV is like 28/29%? My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE (if Ref SD<0.294) and ABE analysis (if Ref SD>0.294)

John
ElMaestro
Hero

Denmark,
2017-03-20 06:55

@ jag009
Posting: # 17167
Views: 262
 

 Highly Variable Drug BE Justification

Hi jag009,

» What if one conducted pilot studies and found that the ISCV is like 28/29%? My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE(if Ref SD<0.294) and ABE analysis(if Ref SD>0.294)

That's valid, but if you are not really sure if you are just "borderline" then the additional overhead associated with the replicated design may not be worth it. You find an intra-CVR of 31%, and you scale the limits a wee bit etc. But the price you paid for this moderate scaling option could be much higher than you'd be paying for a conventional 222BE trial with a few extra volunteers. Would be interesting to discuss an objective function here :-)

This isn' the answer, but just a view.

I could be wrong, but…


Best regards,
ElMaestro


Here's the good news, folks: If you leave operational excellence, (c)LEAN, six sigma and management consultancy firms out of your development programmes, then you may have a chance to be first to market and to beat your competitors.
Helmut
Hero
Homepage
Vienna, Austria,
2017-03-20 13:12

@ ElMaestro
Posting: # 17169
Views: 237
 

 Study costs: Replicate vs. 2×2×2

Hi ElMaestro & John,

» » My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE(if Ref SD<0.294) and ABE analysis(if Ref SD>0.294)

» That's valid, but if you are not really sure if you are just "borderline" then the additional overhead associated with the replicated design may not be worth it. You find an intra-CVR of 31%, and you scale the limits a wee bit etc. But the price you paid for this moderate scaling option could be much higher than you'd be paying for a conventional 222BE trial with a few extra volunteers.

I lean towards John’s idea. Say you estimated the 31% from a previous 2×2×2 study in 40 subjects and assume that CVwR=CVwT=CVw. The 95% CI of the CV is 25.1–40.6%. Hence, in the best case (high CVwR) the FDA’s implied BE-limits would be 70.58–141.69%. That’s rather substantial.

» Would be interesting to discuss an objective function here :-)

Some ideas: The number of treatments in a 2×2×4 study is roughly the same as in a 2×2×2 study – if we don’t plan for reference-scaling (which I likely would do in a borderline case).
  • Equal costs
    • Design & logistics,
    • Ethics committee,
    • Medical writing,
    • Consumables (clinics, bioanalytics),
    • Sample shipment if applicable,
    • Biostatistics.
  • Lower costs
    • Screenings & post-study exams,
    • Subjects’ remuneration (though higher for the individuals due to more samples, extended hospitalization).
  • Higher costs
    • Clinics,
    • Analytics (not necessarily: Roughly the same number of samples but might take longer if a batch size exceeds a working day).
I would not be worried about the higher chance of dropouts in the replicate study. The impact on power is low (unless the drug is nasty and dropouts are caused by AEs).
Calculation of costs is complicated (fixed & variable costs, blahblah). In my CRO we had a spreadsheet with 100 rows… Had a quick look (19 samples / period, last sampling 16 hours; 2×2×2 in 42 subjects vs. 2×2×4 in 22). The replicate design would be ~4% cheaper. ;-) If you hope for RSABE (for CVwR 31% 18 subjects instead of 22 for ABE) the reduction in costs would be ~12%.

[image]All the best,
Helmut Schütz 
[image]

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

Poland,
2017-03-21 12:49

@ Helmut
Posting: # 17172
Views: 138
 

 Study costs: Replicate seems to be cheaper

Hi Helmut,

We were able to get more than 4% discount for replicate versus equivalent '2x2'.

Our internal belief is that replicate is cheaper, but will take more time... And time is money...

We would rather do replicate study instead of large '2x2' with 2 or more groups due to the capacity of the clinic (if wash-out is not long).

Regards, VStus
Dr_Dan
Senior

2017-03-21 13:06

@ VStus
Posting: # 17173
Views: 133
 

 Study costs: Replicate seems to be cheaper

Dear VStus
For your calculation please keep in mind: the more study periods you have the higher the risk of drop outs.

Kind regards and have a nice day
Dr_Dan
Helmut
Hero
Homepage
Vienna, Austria,
2017-03-21 14:50

@ Dr_Dan
Posting: # 17176
Views: 122
 

 Study costs: Replicate seems to be cheaper

Hi Dan,

I agree with VStus.

» For your calculation please keep in mind: the more study periods you have the higher the risk of drop outs.

As I wrote above:
» » I would not be worried about the higher chance of dropouts in the replicate study. The impact on power is low (unless the drug is nasty and dropouts are caused by AEs).

Try:

library(PowerTOST)
CV  <- 0.31
dor <- 5 # dropout-rate (in each washout) in percent
des <- "2x2x2"
res <- sampleN.TOST(CV=0.31, design=des, print=FALSE)
n   <- res[["Sample size"]]
pwr <- res[["Achieved power"]]
wo  <- as.integer(substr(des, nchar(des), nchar(des)))-1
el  <- n # eligible subjects
for (j in 1:wo) {
  el <- el*(1-dor/100)
}
cat("Study started with", n, "subjects (expected power",
    sprintf("%.1f%%).", 100*pwr),
    "\nStudy ended with", as.integer(el), "eligible subjects (expected power",
    sprintf("%.1f%%).", 100*power.TOST(CV=CV, design=des, n=el)), "\n")
# Study started with 42 subjects (expected power 81.1%).
# Study ended with 39 eligible subjects (expected power 79.2%).

des <- "2x2x4"
res <- sampleN.TOST(CV=0.31, design=des, print=FALSE)
n   <- res[["Sample size"]]
pwr <- res[["Achieved power"]]
wo  <- as.integer(substr(des, nchar(des), nchar(des)))-1
el  <- n
for (j in 1:wo) {
  el <- el*(1-dor/100)
}
cat("Study started with", n, "subjects (expected power",
    sprintf("%.1f%%).", 100*pwr),
    "\nStudy ended with", as.integer(el), "eligible subjects (expected power",
    sprintf("%.1f%%).", 100*power.TOST(CV=CV, design=des, n=el)), "\n")
# Study started with 22 subjects (expected power 83.3%).
# Study ended with 18 eligible subjects (expected power 75.1%).

Does it really hurt?

[image]All the best,
Helmut Schütz 
[image]

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

Berlin, Germany,
2017-03-21 15:16

@ Helmut
Posting: # 17177
Views: 112
 

 expected power

Dear All!

Don't confuse the usage of "expected power" here by Helmut with the functions in package PowerTOST which estimate the expected power and / or sample size based on expected power, some sort of Bayesian power, taking into account the uncertainty of an observed point estimate of T vs. R and / or the uncertainty of an observed CV.

See f.i. ?exppower.TOST and references given in that man page.

Regards,

Detlew
mahmoud-teaima
Junior

Cairo, Egypt,
2017-03-23 08:17

@ Helmut
Posting: # 17178
Views: 6
 

 Study costs: Replicate vs. 2×2×2

» Hi Helmut,

» Calculation of costs is complicated (fixed & variable costs, blahblah). In my CRO we had a spreadsheet with 100 rows… Had a quick look (19 samples / period, last sampling 16 hours; 2×2×2 in 42 subjects vs. 2×2×4 in 22). The replicate design would be ~4% cheaper. ;-) If you hope for RSABE (for CVwR 31% 18 subjects instead of 22 for ABE) the reduction in costs would be ~12%.

Can you please help me for in the approximate estimation of cost of bioequivalence study?, would you please send me the template sheet that you use for such calculations.

Greetings.

Mahmoud Teaima, PhD.
Assistant Professor at Department of Pharmaceutics and Industrial Pharmacy.
Vice-director at Center of Applied Research and Advanced Studies (CARAS).
Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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