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Back to the forum  Query: 2018-02-21 12:12 CET (UTC+1h)
 
Mikkabel
Junior

Belgium,
2018-01-23 17:29

Posting: # 18277
Views: 975
 

 Choice of comparator [Design Issues]

Dear All,

I have a question regarding the choice of the comparator to be chosen in a classical CO study.

To summarize, my company get the marketing autorisation for a generic product (Tablet, called T1) based on a PK study demonstrating the bioequivalence versus the original product (called R).
Furthermore, according to the originator's SPC, the recommended dose is 1 or 2 Tablets.

Therefore, the R&D branch of my company would like to develop a new dosage of the product T1 corresponding to 2 tablets of the original product (R) in order to increase patients' comfort and compliance with the treatment (only quantitative change to the active substance). The new proposed dosage will be called T2.

Could you please advise which design should be better for a PK study:
  • CO BE study; T2 versus original product R (2 tablets) or
  • CO BE study; 2 Tablets of T1 vs T2 or
  • Dose-proportional study; T1 vs T2
Hope it clear.....;-)

Thank you in advance for your answer,
Helmut
Hero
Homepage
Vienna, Austria,
2018-01-23 17:40

@ Mikkabel
Posting: # 18278
Views: 859
 

 Line extension

Hi Mikkabel,

Luckily you are not exceeding the recommended dose of the originator. Hence, I would opt for a simple line extension (T2 vs. 2×T1) since you can expect a better match than in BE – which is possible as well (T2 vs. 2×R).
I don’t see how you could perform a dose-proportionality study with just two levels (zero degrees of freedom).

[image]Regards,
Helmut Schütz 
[image]

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mittyri
Senior

Russia,
2018-01-23 18:30

@ Helmut
Posting: # 18282
Views: 849
 

 Proportionality and regression

Hi Helmut,

» I don’t see how you could perform a dose-proportionality study with just two levels (zero degrees of freedom).

But we have more than one observation for each level, so regression is possible, isn't it?

Kind regards,
Mittyri
Helmut
Hero
Homepage
Vienna, Austria,
2018-01-23 18:41

@ mittyri
Posting: # 18283
Views: 846
 

 Proportionality and regression

Hi Mittyri,

» » I don’t see how you could perform a dose-proportionality study with just two levels (zero degrees of freedom).
»
» But we have more than one observation for each level, so regression is possible, isn't it?
Yeah, well, cough… :clap:

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Mikkabel
Junior

Belgium,
2018-01-24 10:17

@ Helmut
Posting: # 18285
Views: 767
 

 Line extension

» Luckily you are not exceeding the recommended dose of the originator. Hence, I would opt for a simple line extension (T2 vs. 2×T1) since you can expect a better match than in BE – which is possible as well (T2 vs. 2×R).
» I don’t see how you could perform a dose-proportionality study with just two levels (zero degrees of freedom).

Hi Helmut,

Thank you for your quick reply!

I would also opt for a simple Pk study (T2 versus 2*T1) but do you have any idea to which guidelines I can refer to justify the rationale of the study and in particular the choice of the comparator (T1 instead of the originator).

Regarding the dose proportional study, I meant a PK study (T1 vs T2) and the results corrected by the dose should be compared.

Kind regards,
Helmut
Hero
Homepage
Vienna, Austria,
2018-01-24 11:56

@ Mikkabel
Posting: # 18287
Views: 769
 

 Type II variation

Hi Mikkabel,

» I would also opt for a simple Pk study (T2 versus 2*T1) but do you have any idea to which guidelines I can refer to justify the rationale of the study and in particular the choice of the comparator (T1 instead of the originator).

See Annex I to EC 1234/2008 about Type II variations …

2. Changes to strength, pharmaceutical form and route of administration:
    (c) change or addition of a new strength/potency;

… and the Q&A about extensions of marketing authorisations.
In the line extensions I was involved in (example) we always used the approved strength of our product as the comparator (and not the innovator’s product).1

» Regarding the dose proportional study, I meant a PK study (T1 vs T2) and the results corrected by the dose should be compared.

I did it once in 2003.2 The German BfArM told me “OK, we accept it this time but please don’t do it in the future…”. Makes perfect sense indeed (I learned): Demonstration of BE requires administration of the same molar dose(s).3

Let T2 = ƒ×T1, F the absolute BA, and R the response in any given PK metric of interest (AUC, Cmax, …).
  • If (!) FT2 ≡ FT1 and CLT2 ≡ CLT1 (a general assumption in BE) then RT2/(ƒ×RT1) = 100%. Brilliant.
  • Now FT2 < FT1 but at the same time we run into saturation of a metabolizing enzyme with the high strength. R will be higher since the drug is slower eliminated (CLT2 < CLT1). If we perform the dose-cor­rection (in the worst case) we get also 100% since the lower F of T2 is “masked” by its lower clearance.
    If we would have administered the same doses we would have seen the lower F of T2.
An example:
DT1 1 (F 100%) ▬▬, DT2 2 (F 90%) ▬▬, and at the high dose elimination is prolonged by ~12% due to saturation.

[image]


If we dose-correct T1 ▬▬, we get for T2 – false – GMR estimates of 100% for AUC0–t, 103% for AUC0–∞, and 94% for Cmax. We wouldn’t adjust individual profiles. I expect that the rather small prolongation of the elimination would not be evident in the data (hidden by biological noise). And no, we would never notice the seven minutes delay in tmax.

However, if we administer the same doses, elimination should be prolonged to a similar extent (CLT2 ≈ CLT1).

[image]


Hence, GMR estimates for all PK metrics would be unbiased (≈90%)4 reflecting the true relative BA.


  1. I’ve heard rumors that in MENA states the originator is preferred by some assessors. If possible, opt for a scientific advice.
  2. It was an intermediate strength and strict dose-proportionality was already established.
  3. BE-GL, Section 1.1:
    Two medicinal products […] are considered bioequivalent if […] their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits.
  4. Due to FT2 < FT1 (less drug in the circulation after T2) we challenge the enzyme less than with 2×T1. Hence, the estimates might be slightly higher than 90%.

[image]Regards,
Helmut Schütz 
[image]

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