Bioequivalence and Bioavailability Forum

unique_one
☆

India,
2015-10-17 11:33
(3493 d 14:14 ago)

Posting: # 15569
Views: 7,599

2 way fasting and 3 way fed pilot results analysis [Study Assessment]

Dear All,

We conducted a fasting (2-way crossover) and fed (3 way reference replicate scaled average BE) pilot studies for one of the molecules.

N=16 for fasting pilot and N=18 for fed pilot.

The results are as below:

Fasting Pilot:

Parameter     Ratios  CI 90_L  CI 90_U  Power   IS CV (%)

Ln(Cmax)      98.58    77.47   128.41   0.4194   43.13

Ln(AUC last)  93.86    82.05   110.32   0.8307   22.51

Ln(AUC INF)   89.75    72.47   111.56   0.5223   33.65

Fed pilot:

Parameter  S_wR   Reference ISCV(%)

Cmax      0.333      33.13%

AUCt      0.244      26.32%

AUCi      0.325      35.48%



Parameter  T/R ratio  theta  95% upper CI

Cmax          0.86     0.79     0.044

AUCi          0.82     0.79     0.143



Parameter RLSM  Test LSM  Ref GM    Test GM    T/R        90% CI       power

AUCt      8.350   8.220   4712.223  4170.343  87.23%  74.25%-106.25%    0.69

Below are the considerations:

As per the literature, this molecule has a food effect and food decreases bioavailability of Cmax and AUC, by approximately 40% - 45% and 20% - 23%, respectively.
This molecule shows high variablity when administered with food and therefore a reference replicate pilot study was planned.

Queries:

Looking to the above results, it is seen that the Test product is behaving fast in comparison to the Reference in fasting pilot study. However in contradiction, the test product is behaving slow in comparison to the reference in fed pilot study.

Do we need to do any change in the formulation at this point? Because any change (fastening/slowing) will effect both fasting and fed pivotal studies.
What would be the sample size recommended for fasting 2 way crossover pivotal study and pivotal fed reference replicate scaled average BE study?
As per my dissolution media results, the product is a bit slower in one of the dissolution media. Any correlation from this aspect?
What should be the best strategy to plan the pivotal studies for above molecule with respect to the current formulation and process and the pivotal studies design so as to get good results in the pivotal studies?

Thanks everyone in Advance.
Unique_One.

Edit: Category changed. Why are you shouting as us? All-capitals ⇒ lowercase. Use series of blanks enclosed in BBCodes instead of tabs. [Helmut]

Mahmoud
★

Jordan,
2015-11-22 10:51
(3457 d 13:56 ago)

(edited on 2015-11-22 23:09)
@ unique_one
Posting: # 15651
Views: 5,322

2 way fasting and 3 way fed pilot results analysis

Post reply

Dear Sir

1. For the pilot fasting study based on N=18. The CV in cmax is >30% then we can use 3 way reference replicate scaled with N=36 or we can use two -stage 2x2 with N=50

2. For fed study: The problem in GMR is about 87%. So in this case I recommened to genrate your study using the full replicate scaled with N=36

Dr.Mahmoud Abdel Mohsen

statistician
Amman-Jordan
[email protected]

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,
2015-11-23 15:01
(3456 d 09:46 ago)

@ Mahmoud
Posting: # 15654
Views: 5,278

Where do these numbers come from?

Post reply

Hi Mahmoud,

❝ Dear Sir

▲ Are you sure that Unique_One is male?

❝ 1. For the pilot fating study based on N=18.

Nope. n=16. :cool:

❝ The CV in cmax is >30% then we can use 3 way reference replicate scaled with N=36

Why 36? For FDA’s RSABE, CV 43.13%, T/R 0.90 (risky to assume a “better” one – even if the pilot suggests so), 80% power:

design n power RTRT|TRTR 18 0.82595 RTR|TRT 28 0.83176 RRT|RTR|TRR 24 0.81442

The FDA requires a minimum sample size of 24, which will give you a power of 0.92498 if all subjects in the 4-period full replicate complete the study.

❝ or we can use two -stage 2x2 with N=50

How did you derive this number? A T/R of 0.9 calls for Montague’s “Method D” (an adjusted α of 0.028). Reference-scaling is not possible in TSDs. One can start the first stage with any number of subjects. A reasonable n₁ is ~¾ of the fixed sample design’s n (with α 0.05: 154). With n₁ 116 power in the first stage is 59.8%, the chance to proceed to the second stage is 39.7%, and overall power is 82.6%. The expected average total sample size is 147. Percentiles of N:

min 5% 25% med 75% 95% max 116 116 116 116 184 222 310

If you start with only 50 subjects, power in the first stage will be just 28.4%, the chance to proceed to #2 is 71.6%, whereas overall power is similar with 81.4%. Generally you can expect higher sample sizes. Average 153 and:

min 5% 25% med 75% 95% max 50 50 50 172 206 252 390

Not a good idea.

❝ 2. For fed study: The problem in GMR is about 87%. So in this case I recommened to genrate your study using the full replicate scaled with N=36

Again: Why 36? Most critical is AUCi with T/R 0.82 (‼) and CV 35.48%. If we believe that these values are true (ha-ha), we would need 146 subjects in a 4-period full replicate. The 36 you suggested would give Unique_One a power of 45.7%. That’s less than the 48.6% winning chance one could expect for betting rouge/noir, pair/impair, manque/passe in roulette. Bad advice.
BTW, the high number is mainly caused by the [0.80–1.25] constraint on the PE. Without (theoretically) we would need 80 subjects.

—
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

Helmut
★★★

Vienna, Austria,
2015-11-23 17:57
(3456 d 06:50 ago)

@ unique_one
Posting: # 15656
Views: 5,166

Numbers?

Post reply

Hi Unique_One,

❝ N=16 for fasting pilot…

❝ Parameter Ratios CI 90_L CI 90_U Power IS CV (%)

❝ Ln(Cmax) 98.58 77.47 128.41 0.4194 43.13

❝ Ln(AUC last) 93.86 82.05 110.32 0.8307 22.51

❝ Ln(AUC INF) 89.75 72.47 111.56 0.5223 33.65

I fail to understand your numbers. The PE should be \(\sqrt{CL_{lower} \times CL_{upper}}\), right? Based on the CIs I got:

PE CV% “power” ln(Cmax) 99.74 42.30 0.0472 ln(AUClast) 95.14 24.11 0.5496 ln(AUCinf) 89.92 35.70 0.0997

Strange. Bizarre rounding? BTW, the useless “power” is completely wrong. Shall I say as usual? Is there an Indian conspiracy to apply a false and outdated method (see this post)? There is a rule of thumb for T/R 0.95 and ≥80% power: n=20 (CV 20%) and n=40 (CV 30%). So why would one expect 83% power for AUClast for n=16? With your reported numbers you would need 26.

—
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

2 way fasting and 3 way fed pilot results analysis [Study As­sess­ment]

2 way fasting and 3 way fed pilot results analysis

Where do these numbers come from?

Numbers?

2 way fasting and 3 way fed pilot results analysis [Study Assessment]