Bioequivalence and Bioavailability Forum

jag009 ★★★ NJ, 2012-05-10 18:14 (4736 d 20:42 ago) Posting: # 8556 Views: 6,901	Sample Size from Interaction study [Power / Sample Size] Post reply
	Hi Helmut, Is it possible to get an estimate of the intrasubject CV from a single dose design drug interaction study? I reviewed your presentation on sample size and you mentioned that CV can be obtained from Cave at steady state? Thanks John Edit: Category changed. [Helmut]

Helmut
★★★

Vienna, Austria,
2012-05-10 18:42
(4736 d 20:14 ago)

@ jag009
Posting: # 8557
Views: 5,746

Sample Size from Interaction study

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Dear John!

❝ Is it possible to get an estimate of the intrasubject CV from a single dose design drug interaction study?

Yes.

❝ I reviewed your presentation on sample size and you mentioned that CV can be obtained from Cave at steady state?

I’m not a native speaker of English. To me as a certified cave diver “Cave at steady state” sounds funny. :-D

I meant the Latin word cave. Generally PK interaction studies are performed in steady state (FDA, EMA). With a few exceptions^* variance in steady state is lower than after a single dose. If you plan a single dose study based on the MD’s CV, your sample size likely will be too low.

Van Hoogdalem EJ, Terpstra IJ, Krauwinkel WJJ, Volkers-Kamermans NJ, Baven ALM, and JSC Verschoor
Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers
Int J Clin Pharmacol Ther 1996;34(5):202–7
PMID 8738856

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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jag009
★★★

NJ,
2012-05-10 21:39
(4736 d 17:17 ago)

@ Helmut
Posting: # 8558
Views: 5,708

Sample Size from Interaction study

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Thanks Helmut,

I back-computed the intra-CV from the single dose interaction study and it was 13-14%. I decided to go with 20% CV as the basis for my sample size estimation. I hope that's not an overkill...

Another question, for truncated AUC0-72 hours, what is your experience in terms of setting the limit for 72 hr blood draw time deviation? The drug has a half-life of 20-30 hours. The clinic allows the subjects to return for the 72 hour return blood draw with a +4 hour time limit (i.e, if they come back after 76 hours then they will not collect it).

Is that a bit too late? I would either set the limit to 1 hour or keep the subject for 72 hours in house.

Thanks

John

Helmut
★★★

Vienna, Austria,
2012-05-11 17:13
(4735 d 21:43 ago)

@ jag009
Posting: # 8560
Views: 5,661

Uncertainty of CVs; AUC72 - actual vs. nominal time

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Hi John!

❝ I back-computed the intra-CV from the single dose interaction study and it was 13-14%. I decided to go with 20% CV as the basis for my sample size estimation. I hope that's not an overkill...

You can take the uncertainty of the CVs into account (smaller for larger studies). Play around in Detlew’s PowerTOST-package (T/R 0.95, 90% power, CV 14% derived from studies with 12 and 24 subjects):

require(PowerTOST)

expsampleN.TOST(targetpower=0.9, CV=0.14, dfCV=12-2, design="2x2")

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

   Sample size est. with uncertain CV

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

Study design:  2x2 crossover 

log-transformed data (multiplicative model)



alpha = 0.05, target power = 0.9

BE margins        = 0.8 ... 1.25 

Null (true) ratio = 0.95

CV                 = 0.14 with 10 df

one-sided upper CL = 0.2247103 (level = 95%)



Sample size (ntotal)

 n    exp. power

18   0.921907



expsampleN.TOST(targetpower=0.9, CV=0.14, dfCV=24-2, design="2x2")

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

   Sample size est. with uncertain CV

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

Study design:  2x2 crossover 

log-transformed data (multiplicative model)



alpha = 0.05, target power = 0.9

BE margins        = 0.8 ... 1.25 

Null (true) ratio = 0.95

CV                 = 0.14 with 22 df

one-sided upper CL = 0.1876612 (level = 95%)



Sample size (ntotal)

 n    exp. power

16   0.931383

So n=20 is reasonable even if the CV was obtained in a small study.

❝ Another question, for truncated AUC0-72 hours, what is your experience in terms of setting the limit for 72 hr blood draw time deviation?

Personally I use the estimated AUC₇₂ whatever the actual sampling time was.

❝ The drug has a half-life of 20-30 hours. The clinic allows the subjects to return for the 72 hour return blood draw with a +4 hour time limit (i.e, if they come back after 76 hours then they will not collect it).

Great for the CRO. You loose power (exclude the subject), the study is more likely to fail, the CRO will perform another study with a larger sample size. Bad idea IMHO.

❝ Is that a bit too late?

Yes; especially if we use the measured C_t. Example: A -100, B 100, t_½,α 1 h, t_½,β 25 h, T/R 100%, simple trapezoidal.

  t       C

 0        BQL

 0.5     27.91

 1       47.27

 2       69.61

 3       79.52

 4       83.25

 5       83.93

 6       83.11

 9       77.72

12       71.67

16       64.17

24       51.41

36       36.86

48       26.43

72       13.58

AUC₇₂ 2996

Let’s assume that after the reference the last sample is drawn at 72 h and after the test at 73 h. AUC₇₃ is 3011, T/R 100.5% – acceptable bias. If the last sample is drawn at 76 h, AUC₇₆ is 3056, T/R 102.0%.
If you are able to estimate λ_z you can use the estimated concentration at 72 h:

Ĉ₇₂ = C_tz · ℯ^{–λ_z(72–t_z)}

From the last three concentrations we get half lives of 24.99 h and 25.00 h, pretty close to the theoretical 25 h. Estimated 72 h-concentrations are 13.58 (last sample 73 h) and 13.59 (last sample 76 h) leading to estimated AUC₇₂ of 2996 for both schedules. T/R 100% – bingo.

❝ I would either set the limit to 1 hour or keep the subject for 72 hours in house.

Better (see above). I would prefer the latter – especially if you don’t want to deal with estimated values.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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jag009
★★★

NJ,
2012-05-11 18:36
(4735 d 20:20 ago)

@ Helmut
Posting: # 8561
Views: 5,707

Uncertainty of CVs; AUC72 - actual vs. nominal time

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Thanks Helmut,

I went with T/R ratio 90%, power 90 and came up with something like 36-40 subjects. I added a few more in case of dropouts due to the washout.

About the AUC_0-72. I did some calculation & modeling based on the t_1/2, T_max and gave the CRO a time limit of 30 mins for the 72 hour return blood draw. That is subject will be dropped from the study if they miss the cutoff time collection for the 72 hours in period 1, or their data will not be included in the stat analysis if they complete both periods but missing 72 hour sample in period 2. If the CRO can't do that then my threshold is 1 hour. One hour is acceptable since I did a comparison between AUC_0-72 and AUC_0-73 based on t_1/2 of 25-40 hours and the difference is less than 1%. Their limit of 4 hour is way too long. Otherwise I will ask to have them subjects housed for 72 hours. I don't want to mess around with a BE assessment.

John

PS. It's Friday here! :smoke:

Do you have the drinking smiley?

Helmut
★★★

Vienna, Austria,
2012-05-11 19:35
(4735 d 19:21 ago)

@ jag009
Posting: # 8562
Views: 5,664

Uncertainty of CVs; AUC72 - actual vs. nominal time

Post reply

Hi John!

❝ I went with T/R ratio 90%, power 90 and came up with something like 36-40 subjects. I added a few more in case of dropouts due to the washout.

I got:

require(PowerTOST)

expsampleN.TOST(targetpower=0.9, theta0=0.9, CV=0.14, dfCV=12-2, design="2x2")

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

   Sample size est. with uncertain CV

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

Study design:  2x2 crossover

log-transformed data (multiplicative model)



alpha = 0.05, target power = 0.9

BE margins        = 0.8 ... 1.25

Null (true) ratio = 0.9

CV                 = 0.14 with 10 df

one-sided upper CL = 0.2247103 (level = 95%)



Sample size (ntotal)

 n    exp. power

32   0.901134

With >40 you should be on the safe side.

❝ […] I did some calculation & modeling based on the t_1/2, T_max and gave the CRO a time limit of 30 mins for the 72 hour return blood draw.

OK.

❝ That is subject will be dropped from the study if they miss the cutoff time collection for the 72 hours in period 1, or their data will not be included in the stat analysis if they complete both periods but missing 72 hour sample in period 2. If the CRO can't do that then my threshold is 1 hour.

You are aware that you may loose power according to this procedure? What if the CRO want’s to make money (they all do)¹ and tell the subjects “Don’t worry too much about the 72 hours, especially in the second period.” Maybe you see some ‘personal reasons’ for coming late of the type

There was a traffic jam – I couldn’t make it earlier.
My bike was stolen. Didn’t know that public transportation is such a nightmare in this area!²
Aunt Lizzie went to hospital and I had to hush my mother on the phone.
Seeing a squirrel my cat panicked and I had to fetch her from the rain pipe.

❝ One hour is acceptable since I did a comparison between AUC_0-72 and AUC_0-73 based on t_1/2 of 25-40 hours and the difference is less than 1%.

Confirmed.

❝ Their limit of 4 hour is way too long. Otherwise I will ask to have them subjects housed for 72 hours.

Supported.

❝ I don't want to mess around with a BE assessment.

Yep! Probably would need a strong stand against the FDA.

❝ […] Do you have the drinking smiley?

I added this one: :party:

If you prefer other virtual drinks, let me know.

“We are really terribly sorry that the study did not pass due to so many excluded subjects. Do you want to repeat it in a larger sample size?”
Flimsy excuse. Public transportation is a nightmare everywhere in the US, IMHO.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

jag009
★★★

NJ,
2012-05-11 20:13
(4735 d 18:43 ago)

@ Helmut
Posting: # 8563
Views: 5,640

Uncertainty of CVs; AUC72 - actual vs. nominal time

Post reply

❝ You are aware that you may loose power according to this procedure? What if the CRO want’s to make money (they all do)¹ and tell the subjects.

Well I don't forsee that big of a problem and I think 1 hour is more than reasonable. I haven't seen a study so far which has subjects with a > 1 hr deviation on sample collection time.

Cost will be the problem if we have to house the subject for 72 hours. I need to run fast and fed studies (for 2 strengths, not proportional).. I agree that we can go down on sample size to compensate...

❝ 1. “We are really terribly sorry that the study did not pass due to so many excluded subjects. Do you want to repeat it in a larger sample size?”

❝ 2. Flimsy excuse. Public transportation is a nightmare everywhere in the US, IMHO.

More like tough luck, that is the client's problem so just pay us and we wil rerun the study. Hey I am runnig with 48 subjects! BTW, not running in US though. :-|

Yes it's Friday! :party:

Sample Size from Interaction study [Power / Sample Size]

Sample Size from Interaction study

Sample Size from Interaction study

Uncertainty of CVs; AUC72 - actual vs. nominal time

Uncertainty of CVs; AUC72 - actual vs. nominal time

Uncertainty of CVs; AUC72 - actual vs. nominal time

Uncertainty of CVs; AUC72 - actual vs. nominal time