Bioequivalence and Bioavailability Forum

Ken Peh ★ Malaysia, 2013-02-16 17:26 (4860 d 13:28 ago) Posting: # 10045 Views: 9,351	Trifluoperazine [Design Issues] Post reply
	Dear All, May I know if anyone has experience with trifluoperazine ? Is this a highly variable drug ? We would like to carry out BE study on trifluoperazine. Nevertheless, we could highly find sufficient information on this drug. The sponsor is reluctant to carry out pilot study since pilot study incurs extra cost and furthermore it is a generic product. Thank you in advance. Regards, Ken

drgunasakaran1
★★

2013-02-17 09:53
(4859 d 21:01 ago)

@ Ken Peh
Posting: # 10047
Views: 8,205

Trifluoperazine

Post reply

Dear Mr Ken,

❝ Nevertheless, we could highly find sufficient information on this drug.

There are only limited information available regarding the variability of Trifluoperazine. As per the literature, Peak plasma concentrations varied widely (range 0.53-3.09 ng/ml) and were reached 2.8 +/- 0.5 h following ingestion of the Trifluoperazine tablet. The area under the plasma concentration-time curve differed widely between subjects (range: 5.9-17.6 ng ml-1 h) suggesting large individual differences in the extent of presystemic Trifluoperazine elimination.

Reference

—
Dr Gunasakaran Sambandan MD
Disclaimer: The replies/posts are my personal opinions, and they do not represent my company's views on the same. LinkedIn

Ken Peh ★ Malaysia, 2013-02-18 08:28 (4858 d 22:27 ago) (edited on 2013-02-18 09:33) @ drgunasakaran1 Posting: # 10048 Views: 8,021	Trifluoperazine Post reply
	Dear Dr Gunasakaran, TQVM for the useful information. Then, how do we estimate the sample size to achieve at least 80% power for BE study on this drug ? Grateful if you could kindly enlighten me. Regards, Ken 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! [Ohlbe]

Helmut
★★★

Vienna, Austria,
2013-02-18 14:53
(4858 d 16:01 ago)

@ Ken Peh
Posting: # 10049
Views: 8,018

Pilot or Two-Stage

Post reply

Dear Ken!

❝ Then, how do we estimate the sample size to achieve at least 80% power for BE study on this drug ?

The 30years old paper does not help. After 5mg in five (!) subjects CV_total of C_max 93% and of AUC_t 51%… You need CV_intra from a cross-over study.

IMHO you have two options:

Perform a pilot study which will (after drop-outs) > the minimum sample size in your regulation (Malaysia: 12). State in the protocol that if you are able to show BE already in the pilot the study will act as the pivotal study.
Perform a Two-Stage Sequential Design (see e.g., this presentation). Ask your authority whether such a design is acceptable. The Malaysian GL from 2000 of course does not cover such a design.

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Ken Peh
★

Malaysia,
2013-02-18 19:19
(4858 d 11:35 ago)

@ Helmut
Posting: # 10052
Views: 8,222

Pilot or Two-Stage

Post reply

Dear Helmut,

❝ The 30years old paper does not help. After 5mg in five (!) subjects CV_total of C_max 93% and of AUC_t 51%… You need CV_intra from a cross-over study.

Understood. TQVM.

❝ IMHO you have two options:

❝ • Perform a pilot study which will (after drop-outs) > the minimum sample size in your regulation (Malaysia: 12). State in the protocol that if you are able to show BE already in the pilot the study will act as the pivotal study.

Do you mean if we use 20 subjects (>12) and able to show BE although the power is less than 80%, we can switch from pilot to pivotal ? How to justify to the regulatory agency on this ?

❝ • Perform a Two-Stage Sequential Design (see e.g., this presentation). Ask your authority whether such a design is acceptable. The Malaysian GL from 2000 of course does not cover such a design.

Yes, the new ASEAN guideline addresses this. Thank you for the presentation. Will digest the information.

Highly appreciate your kind assistance.

Best Regards,
Ken

Helmut
★★★

Vienna, Austria,
2013-02-19 14:37
(4857 d 16:17 ago)

@ Ken Peh
Posting: # 10056
Views: 8,068

Pilot or Two-Stage

Post reply

Dear Ken!

❝ ❝ • Perform a pilot study which will (after drop-outs) > the minimum sample size in your regulation (Malaysia: 12). State in the protocol that if you are able to show BE already in the pilot the study will act as the pivotal study.

❝

❝ Do you mean if we use 20 subjects (>12) and able to show BE although the power is less than 80%, we can switch from pilot to pivotal ? How to justify to the regulatory agency on this ?

The sample size should be as large that after excluding drop-outs you have still 12 evaluable subjects. In how many you actually start depends on the AE-profile of the drug. I would consider it unethical to perform a pivotal study when you have already shown BE in the pilot. Of course your intention to do so has to be stated in the protocol.

❝ ❝ • Perform a Two-Stage Sequential Design (see e.g., this presentation). Ask your authority whether such a design is acceptable. The Malaysian GL from 2000 of course does not cover such a design.

❝

❝ Yes, the new ASEAN guideline addresses this.

Do you have a reference? The newest version I know is the 2004 ‘final draft’. BTW, the 2009 Q&A-document v2 is in error:

Q: How is the required number of subjects determined?
A: The number of subjects required is determined by:

the intra-subject coefficient of variation of the drug to be studied either estimated from a pilot study, results of previous clinical studies or from published literature.
the significance level desired (α=0.05)
the expected deviation from the reference product compatible with bioequivalence (delta, ie percentage difference from 100% ie. ±20%)
the required power should be at least 80%

The clinical and analytical standards imposed may also influence the statistically determined number of subjects. However, generally the minimum number of subjects should not be smaller than 12.

If one expects a deviation of ±20% (c) the samples size has to be infinity even for a CV of zero. ;-)

Should read “ie ±5%”.

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Ken Peh
★

Malaysia,
2013-02-20 04:34
(4857 d 02:20 ago)

@ Helmut
Posting: # 10072
Views: 7,878

Pilot or Two-Stage

Post reply

Dear Helmut,

❝ The sample size should be as large that after excluding drop-outs you have still 12 evaluable subjects. In how many you actually start depends on the AE-profile of the drug. I would consider it unethical to perform a pivotal study when you have already shown BE in the pilot. Of course your intention to do so has to be stated in the protocol.

Do you mean even we can not achieve the power (>80%) as long as BE is proven ??? Am I correct?

❝ Do you have a reference?

I do not have newer version. Nevertheless, the 2013 ASEAN Guideline on BA/BE will be out soon.

❝ If one expects a deviation of ±20% (c) the samples size has to be infinity even for a CV of zero. ;-) Should read “ie ±5%”.

I am sorry. Could you please kindly elaborate the last sentence."If one expects a deviation of ±20%, the samples size has to be infinity even for a CV of zero. Should read “ie ±5%".

Regards,
Ken

Helmut
★★★

Vienna, Austria,
2013-02-20 21:11
(4856 d 09:43 ago)

@ Ken Peh
Posting: # 10087
Views: 7,864

Post hoc power & other things…

Post reply

Dear Ken!

❝ Do you mean even we can not achieve the power (>80%) as long as BE is proven ??? Am I correct?

Post hoc power is completely irrelevant in bioequivalence. Either you demonstrated BE or not. Full :stop:

. Unfortunately the Malaysian authority asks for post hoc power sometimes (or always?). It’s time for them to learn. ;-)

❝ Nevertheless, the 2013 ASEAN Guideline on BA/BE will be out soon.

THX! Would you be so kind to post a link once the GL is published?

❝ ❝ If one expects a deviation of ±20% (c) the samples size has to be infinity even for a CV of zero. ;-) Should read “ie ±5%”.

❝

❝ I am sorry. Could you please kindly elaborate the last sentence. "If one expects a deviation of ±20%, the samples size has to be infinity even for a CV of zero. Should read “ie ±5%".

The wording of the Q&A document is nonsense, whereas the 2004 GL is correct:

The number of subjects required is determined by

the error variance associated with the primary characteristic to be studied as estimated from a pilot experiment, from previous studies or from published data,
the significance level desired,
the expected deviation from the reference product compatible with bioequivalence (delta, ie percentage difference from 100 %) and
the required power.

“Delta” mentioned in (c) is the expected deviation of test from reference. In many cases 5% (a T/R-ratio of 95%) is used. If you expect a deviation of 20% (ratio 80%) it is simply very, very unlikely to show BE – even if you include the entire population of our planet in the study… OK, the actual ratio in a given study might be >80% just by chance, but you cannot seriously plan a study for such a deviation. Examples (very, very low CV of just 5%):

library(PowerTOST)

sampleN.TOST(CV=0.05, theta0=0.8)

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

            Sample size estimation

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

Study design:  2x2 crossover 

Error: Null ratio 0.8 not between margins 0.8 / 1.25!



sampleN.TOST(CV=0.05, theta0=0.8000021)

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

            Sample size estimation

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

Study design:  2x2 crossover

log-transformed data (multiplicative model)



alpha = 0.05, target power = 0.8

BE margins        = 0.8 ... 1.25

Null (true) ratio = 0.8000021,  CV = 0.05



Sample size (total)

 n     power

4480622660   0.800000

↑ Would require more than the entire population of Asia (4.26 billions).

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Ken Peh
★

Malaysia,
2013-02-22 09:17
(4854 d 21:37 ago)

@ Helmut
Posting: # 10101
Views: 7,818

Post hoc power & other things…

Post reply

Dear Helmut,

❝ Post hoc power is completely irrelevant in bioequivalence. Either you demonstrated BE or not. Full :stop: . Unfortunately the Malaysian authority asks for post hoc power sometimes (or always?). It’s time for them to learn. ;-)

Yes, it is a requirement. Please refer to Guidelines on Bioequivalence, 7.Bioequivalence Reporting Format (under 9.4) http://portal.bpfk.gov.my/index.cfm?&menuid=122.

❝ THX! Would you be so kind to post a link once the GL is published?

Sure, I will do it.

❝ alpha = 0.05, target power = 0.8

❝ BE margins = 0.8 ... 1.25

❝ Null (true) ratio = 0.8000021, CV = 0.05

❝

❝ Sample size (total)

❝ n power

❝ 4480622660 0.800000

❝ ↑ Would require more than the entire population of Asia (4.26 billions).

Thank you for the example. I understand now.

Where can we learn how to run PowerTOST ? Please advise.

TQVM.

Regards,
Ken

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! [Helmut]

Helmut
★★★

Vienna, Austria,
2013-02-22 15:15
(4854 d 15:40 ago)

@ Ken Peh
Posting: # 10107
Views: 7,874

Post hoc power & other things…

Post reply

Dear Ken!

❝ ❝ Post hoc power is completely irrelevant in bioequivalence. Either you demonstrated BE or not. Full :stop: . Unfortunately the Malaysian authority asks for post hoc power sometimes (or always?). It’s time for them to learn. ;-)

❝

❝ Yes, it is a requirement. Please refer to Guidelines on Bioequivalence, 7.Bioequivalence Reporting Format (under 9.4) http://portal.bpfk.gov.my/index.cfm?&menuid=122.

Fantastic! Another example where a GL mandates nonsense. However, I cannot find a requirement that post hoc power has to be ≥80%. So, report it based on the study’s T/R-ratio and CV_intra in order to make BPFK happy. If they reject a study which has demonstrated BE (CI within acceptance range) based on power <80% consider going to court.
Section 9.4 contains another stupidity: Summary of statistical significance for AUC and C_max.
In BE we accept 20% as clinically irrelevant. If a study has high power (most likely if the CV is low and/or the T/R-ratio is close to 100%) we might get a statistically significant difference. Again, reporting this outcome is nonsense. See this thread and especially this example.

❝ Where can we learn how to run PowerTOST ? Please advise.

See this post. The help-system will give you all the necessary steps. At the end of each page you find examples. If you are interested in the statistical background see BE_power_sample_size_excerpt.pdf in the folder PowerTOST/doc.

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Ken Peh
★

Malaysia,
2013-02-24 10:08
(4852 d 20:46 ago)

@ Helmut
Posting: # 10113
Views: 7,816

Post hoc power & other things…

Post reply

Dear Helmut,

❝ Fantastic! Another example where a GL mandates nonsense. […]

Thank you for your guidance.

❝ See this post.

Thank you. I have already downloaded and followed your examples to try out PowerTOST. Will use it in future for sample size and power calculation.

Regards,
Ken

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! [Helmut]

Helmut
★★★

Vienna, Austria,
2013-02-24 18:09
(4852 d 12:46 ago)

@ Ken Peh
Posting: # 10116
Views: 7,659

estimation ≠ calculation

Post reply

Dear Ken!

❝ Will use it in future for sample size and power calculation.

Since the CV and T/R-ratio are uncertain values (best case) or only assumptions (worst case) we should avoid the term “calculation” and use “estimation” instead. :-D

</nitpicking>

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Trifluoperazine [Design Issues]

Trifluoperazine

Trifluoperazine

Pilot or Two-Stage

Pilot or Two-Stage

Pilot or Two-Stage

Pilot or Two-Stage

Post hoc power & other things…

Post hoc power & other things…

Post hoc power & other things…

Post hoc power & other things…

estimation ≠ calculation