Vaibhav
☆    

India,
2022-06-20 15:07
(9 d 02:40 ago)

Posting: # 23067
Views: 284
 

 Regulatory acceptance pre-mature discontinuation of study [Study Per­for­mance]

Dear All,

We have been doing patient PK study for USFDA submission and as per protocol we are supposed to enroll 40 subjects and 36 should complete both periods.

So far we have enrolled 37 subjects since pre-valence of diseases covered in study is rare and limitations of site selection. Moreover 06 subjects were discontinued from study. Thus only 31 subjects will be considered for stat. analysis.

Now, situation is Reference product got expired and if we want to procure another lot of reference product for remaining 03 subjects then the cost would be 10 million.
  1. Can we stop the study with 37 subjects and perform stat. analysis with 31 subjects?
  2. Does FDA accept this type of study if we perform analysis with 31 subjects and file pre-plan deviation.
  3. If we procure another lot of reference product then should we keep retention samples 30 capsules?
  4. What will be the anticipated challenges w.r.t. stat. analysis or regulatory acceptance?

Please guide us on above context.

Thank you.


Edit: Category changed; see also this post #1[Helmut]
Helmut
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Vienna, Austria,
2022-06-20 16:13
(9 d 01:35 ago)

@ Vaibhav
Posting: # 23068
Views: 262
 

 Regulatory acceptance pre-mature discontinuation of study

Hi Vaibhav,

which assumptions (CV, T/R-ratio) and target power lead to the sample size?

» We have been doing patient PK study for USFDA submission and […] 36 should complete both periods.
» So far we have enrolled 37 subjects since pre-valence of diseases covered in study is rare and limitations of site selection. […] only 31 subjects will be considered for stat. analysis.
» Now, situation is Reference product got expired and if we want to procure another lot of reference product for remaining 03 subjects then the cost would be 10 million.

Apart from the cost, using different batches in a study is not acceptable. See below why there are no problems expected with 31 subjects. Send me a check for $ 500,000 (peanuts) for delivering the soothing news.

» 1. Can we stop the study with 37 subjects and perform stat. analysis with 31 subjects?

Yes.

» 2. Does FDA accept this type of study if we perform analysis with 31 subjects and file pre-plan deviation.

Why not? Your sample size was based on an assumed recruitment rate and an anticipated dropout-rate. You can’t be blamed if assumptions are not realized in a study. Happens all the time. A smaller sample size does not affect the patient’s risk \(\small{\alpha}\) (the only thing regulators are interested in) – it increases only \(\small{\beta}\), the producer’s risk of failure.

Say, you assumed a CV of 24%, a T/R-ratio of 0.95, and targeted at least 90% power \(\small{(\pi=1-\beta)}\).

library(PowerTOST)
# change the values below to yours
CV     <- 0.24
theta0 <- 0.95
target <- 0.90
design <- "2x2"
plan   <- sampleN.TOST(CV = CV, theta0 = theta0, targetpower = target, design = design)


You get:
+++++++++++ Equivalence test - TOST +++++++++++
            Sample size estimation
-----------------------------------------------
Study design: 2x2 crossover
log-transformed data (multiplicative model)

alpha = 0.05, target power = 0.9
BE margins = 0.8 ... 1.25
True ratio = 0.95,  CV = 0.24

Sample size (total)
 n     power
36   0.914510


What will happen if you have just 31 eligible subjects?
elig  <- 31
power <- suppressMessages(power.TOST(CV = CV, theta0 = theta0, design = design, n = elig))
fmt1  <- "%5.2f%%"
fmt2  <- "(n = %.0f)"
cat("Planned power:", sprintf(fmt1, 100 * plan[["Achieved power"]]),
    sprintf(fmt2, plan[["Sample size"]]),
    "\nActual power :", sprintf(fmt1, 100 * power), sprintf(fmt2, elig),
    "\nRelative loss:",
    sprintf(fmt1, 100 * (1 - power / plan[["Achieved power"]])), "\n")


You get:
Planned power: 91.45% (n = 36)
Actual power : 87.14% (n = 31)
Relative loss:  4.71%


Would such a relative loss in power really hurt?
Recall that the CV and the T/-ratio were assumptions as well. Power is much more sensitive to deviations of these parameters than the sample size. See also this article.


» 3. If we procure another lot of reference product then should we keep retention samples 30 capsules?

Forget it (see above).

» 4. What will be the anticipated challenges w.r.t. stat. analysis or regulatory acceptance?

None.

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Vaibhav
☆    

India,
2022-06-21 14:26
(8 d 03:22 ago)

@ Helmut
Posting: # 23071
Views: 190
 

 Regulatory acceptance pre-mature discontinuation of study

» which assumptions (CV, T/R-ratio) and target power lead to the sample size?

T/R ratio- 95%
Power ≥ 80%
CV%- 25%

One statement they mentioned in protocol “Additional subjects may be randomized in case of excessive drop outs, to get at least 36 subjects with complete pharmacokinetic assessment if required”

» Apart from the cost, using different batches in a study is not acceptable. See below why there are no problems expected with 31 subjects. Send me a check for $ 500,000 (peanuts) for delivering the soothing news.

:-D

For Eg. If we compare New RLD dissolution data Vs OLD RLD dissolution data. And if we found dissolution data of both RLDs is comparable. Still can’t we use new lot of RLD?

» » 1. Can we stop the study with 37 subjects and perform stat. analysis with 31 subjects?
» Yes.

Good.

» » 2. Does FDA accept this type of study if we perform analysis with 31 subjects and file pre-plan deviation.
» Why not? Your sample size was based on an assumed recruitment rate and an anticipated dropout-rate.
»

[…]
» Planned power: 91.45% (n = 36)
» Actual power : 87.14% (n = 31)
» Relative loss:  4.71%
»
» Would such a relative loss in power really hurt?


NO

Development of Abbreviated New Drug Applications During the COVID-19 Pandemic mentions April 2021. Updated on September 8, 2021.
“It may be acceptable to utilize a different batch of unexpired reference product to complete a BE study, so long as the prospective applicant provides adequate scientific justifications for the use of different batches of reference product in the BE studies. A prospective applicant that intends to use a different batch of reference product for such purposes may submit additional inquiries with specific proposals or alternative proposals to demonstrate BE for the development program via the controlled correspondence pathway or, if applicable, via the pre-ANDA meeting request pathway”


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5[Helmut]
Helmut
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Vienna, Austria,
2022-06-21 15:12
(8 d 02:35 ago)

@ Vaibhav
Posting: # 23072
Views: 185
 

 Regulatory acceptance pre-mature discontinuation of study

Hi Vaibhav

» » which assumptions (CV, T/R-ratio) and target power lead to the sample size?
»
» T/R ratio- 95%
» Power ≥ 80%
» CV%- 25%

Here I can’t follow you. Why did you try to recruit 40 subjects in order to have 36 eligible? If your assumptions were reasonable, 28 would have been enough (80.7% power). If you stop with 31 now, power will be with 84.6% higher than expected. I’m confused.

» One statement they mentioned in protocol “Additional subjects may be randomized in case of excessive drop outs, to get at least 36 subjects with complete pharmacokinetic assessment if required”

Such a phrase is not uncommon.

» Development of Abbreviated New Drug Applications During the COVID-19 Pandemic mentions April 2021. Updated on September 8, 2021.
» “It may be acceptable to utilize a different batch of unexpired reference product to complete a BE study, so long as the prospective applicant provides adequate scientific justifications for the use of different batches of reference product in the BE studies. A prospective applicant that intends to use a different batch of reference product for such purposes may submit additional inquiries with specific proposals or alternative proposals to demonstrate BE for the development program via the controlled correspondence pathway or, if applicable, via the pre-ANDA meeting request pathway”

THX, I’ve forgotten that one. If it will cost you 10 million bucks (why on earth?), go ahead but after initiating a Controlled Correspondence with the OGD.

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Helmut Schütz
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dshah
★    

India/United Kingdom,
2022-06-23 12:52
(6 d 04:55 ago)

@ Helmut
Posting: # 23073
Views: 120
 

 Regulatory acceptance pre-mature discontinuation of study

Dear Vaibhav!
From your initial post, I assume the study is required to be performed in diseased condition and anticipate a steady state condition instead of single dose. Further, standardization of patient might be required and thus higher number of dose compensation for patient might be required. Thus, the dropout consideration might be high. What is really surprising, if I am understanding correct than, the assumed T/R and ISCV.
We had faced slightly different condition for NTI drug where RLD got expired during COVID period, and drop out was high due to +ve subjects. For one parameter, the acceptance criteria was not met as per FDA, and the study was rejected.
Addition of new lot of RLD will greatly increase complexity of statistics, too.
Regards,
Divyen Shah
Vaibhav
☆    

India,
2022-06-23 20:41
(5 d 21:07 ago)

@ dshah
Posting: # 23076
Views: 99
 

 Regulatory acceptance pre-mature discontinuation of study

Thank you HS and Dr. Shah for the response.


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5[Helmut]
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