Bioequivalence and Bioavailability Forum • Case Study (FDA)

Helmut
★★★

Vienna, Austria,
2014-09-30 15:02
(3878 d 20:42 ago)

Posting: # 13620
Views: 9,790

Case Study (FDA) [RSABE / ABEL]

Dear all,

in a recently published book* I found an interesting case study. Formulation change of the innovator (mesalamine: DR tablet ⇒ DR capsule). PK endpoints C_max, AUC_0–t, AUC_8–48. Fully replicated 4-period study, 238 (‼) completers, study passed RSABE:

PK metric   s_WR     PE   95% UCL

C_max       1.231  1.11  -1.030

AUC_0–t     1.439  1.10  -1.265

AUC_8–48     1.360  1.08  -1.608

CVs were for C_max (R 200%, T 170%), AUC_t (R 306%, T 272%), and AUC_8-48 (R 286%, T 268%). I guess the originator was well aware about the GMRs in designing the study. For GMR 1.10, CV 300%, and a target power of 90% I got:

++++++++ Reference scaled ABE crit. +++++++++

           Sample size estimation

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

Study design:  2x2x4 (full replicate) 

log-transformed data (multiplicative model)

1e+05 studies for each step simulated.



alpha  = 0.05, target power = 0.9

CVw(T) = 3; CVw(R) = 3

Null (true) ratio = 1.1

ABE limits / PE constraints = 0.8 ... 1.25 

Regulatory settings: FDA



Sample size

 n    power

234   0.90046

Quote:

[…] although the RSABE was implemented to promote development of generic HV drugs by easing regulatory burdens, this was the first time that the approach was successfully used to support major post-approval reformulation of an innovator’s MR drug product.

Note that in the EU scaling is acceptable only for C_max. Good luck with ABE for the AUCs.

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

            Sample size estimation

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

Study design:  2x2x4 replicate crossover 

log-transformed data (multiplicative model)



alpha = 0.05, target power = 0.9

BE margins        = 0.8 ... 1.25

Null (true) ratio = 1.1,  CV = 3



Sample size (total)

 n     power

1208   0.900182

Davit BM, Patel DT. Bioequivalence of Highly Variable Drugs. In: Yu LX, Li BV (eds), FDA Bioequivalence Standards. New York: aapspress/Springer; 2014. p. 139–64. doi 10.1007/978-1-4939-1252-0

—
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, 2014-09-30 19:25 (3878 d 16:19 ago) @ Helmut Posting: # 13622 Views: 8,044	Case Study (FDA) Post reply
	Hi Helmut! What is the different between DR capsule and DR tablet? Hmm... We made capsule formulation containing DR beads and later made a BE tablet formulation containing the same DR beads. Wonder if it is the same thing... ~2-300% ISCV? Crazy... John

Helmut
★★★

Vienna, Austria,
2014-09-30 22:09
(3878 d 13:36 ago)

@ jag009
Posting: # 13624
Views: 8,153

Case Study (FDA)

Post reply

Hi John,

❝ What is the different between DR capsule and DR tablet?

Safety concerns about the plasticizer:
Dibutyl phtalate (NDA 19651) ⇒ dibutyl sebacate (NDA 204412).
The study was performed in three centers, 252 subjects, 238 completed. Details here.

[image]

Oh, how I love arithmetic means ± SDs. If I take this drug must I fear a concentration of ▬300 ng/mL? Antimatter part of the recipe?

❝ ~2-300% ISCV? Crazy...

Absolutely. These are the highest numbers I ever have seen. BTW, AUC > C_max…

—
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

luvblooms
★★

India,
2014-10-01 08:24
(3878 d 03:20 ago)

@ Helmut
Posting: # 13626
Views: 8,124

Case Study (FDA)

Post reply

Hi HS,

❝ Absolutely. These are the highest numbers I ever have seen. BTW, AUC > C_max…

And that too in fasting condition.

I am now more worried about the variability in fed condition where there will be more variables (different gastric pHs, different gastric emptying rate, different gastric moment). Innovator has not done the fed study but FDA want generics company to do both the studies (here)

;-)

With this variability, does it really makes a sense to run a pilot study using 18-24 volunteer?? As there will be no gurantee that a product formula comfortable in pilot will pass again in pivotal studies.

Or one shall simplay go ahead with the exhibit batches and take a rist with higher number of volunteers?

Tough times ahead.

—
~A happy Soul~

Helmut
★★★

Vienna, Austria,
2014-10-01 16:32
(3877 d 19:12 ago)

@ luvblooms
Posting: # 13634
Views: 8,070

Case Study (FDA)

Post reply

Hi Luv,

❝ I am now more worried about the variability in fed condition where there will be more variables (different gastric pHs, different gastric emptying rate, different gastric moment). Innovator has not done the fed study but FDA want generics company to do both the studies (here)

That’s bizarre, IMHO. I didn’t look in the label but in Europe the SmPC states something like “to be taken on an empty stomach one hour before meals”.*

❝ With this variability, does it really makes a sense to run a pilot study using 18-24 volunteer?? As there will be no gurantee that a product formula comfortable in pilot will pass again in pivotal studies.

Likely. We face this problem all the time when we plan pivotal studies. If scaling is concerned, the CV is not problematic, but the GMR really may hurt. With such a high CV, I have some doubts whether you’ll get a meaningful estimate of the GMR from the pilot at all. Follow your gut feelings (mesalamine…). ;-)

❝ Or one shall simplay go ahead with the exhibit batches and take a rist with higher number of volunteers?

Duno. Ask a fortune-teller.

Must correct myself: Neither the US label of the new formulation nor the SmPC in Europe (the “old” formulation is still on the market) contain a statement about food intake. So the recommendation of fasting/fed is in line with what regulators generally want to see for MR-products. Yes, innovators might be treated differently (at least by the FDA).

—
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

luvblooms ★★ India, 2014-10-01 08:15 (3878 d 03:29 ago) @ jag009 Posting: # 13625 Views: 8,051	Case Study (FDA) Post reply
	Hi John ❝ We made capsule formulation containing DR beads and later made a BE tablet formulation containing the same DR beads. What was the ISCV observed? In one of our current study of DR pellets we got IntraSCV ~110% for reference and test (T/R min and max ranges was 8%-4000%) where as the interSCV was ~100% for both. — ~A happy Soul~

jag009
★★★

NJ,
2014-10-01 22:41
(3877 d 13:03 ago)

@ luvblooms
Posting: # 13637
Views: 7,925

Case Study (FDA)

Post reply

Hi Luv,

❝ What was the ISCV observed?

❝ In one of our current study of DR pellets we got IntraSCV ~110% for reference and test (T/R min and max ranges was 8%-4000%) where as the interSCV was ~100% for both.

Not big, less than 20%, maybe like 15%? It was diltiazem. Basically we started the project with DR (or ER) beads in a capsule formulation but then switched to a tablet formulation containing the same ER beads (We called it a wax tablet). It was dead on bioequivalence with T/R Ratio like 95-99%.

John