## Type II variation [Design Issues]

Hi Mikkabel,

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

In the line extensions I was involved in (example) we always used the approved strength of

I did it once in 2003.

Let T

D

If we dose-correct T

However, if we administer the same doses, elimination should be prolonged to a similar extent (CL

Hence, GMR estimates for all PK metrics would be unbiased (≈90%)

❝ 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;

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 T

_{2}= ƒ×T_{1}, F the absolute BA, and R the response in any given PK metric of interest (AUC, C_{max}, …).- If (!) F
_{T2}≡ F_{T1}and CL_{T2}≡ CL_{T1}(a general assumption in BE) then R_{T2}/(ƒ×R_{T1}) = 100%. Brilliant.

- Now F
_{T2}< F_{T1}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 (CL_{T2}< CL_{T1}). If we perform the dose-correction (in the worst case) we get also 100% since the lower F of T_{2}is “masked” by its lower clearance.

If we would have administered the same doses we would have seen the lower F of T_{2}.

D

_{T1}1 (F 100%) ▬▬, D_{T2}2 (F 90%) ▬▬, and at the high dose elimination is prolonged by ~12% due to saturation.If we dose-correct T

_{1}▬▬, we get for T_{2}– false – GMR estimates of 100% for AUC_{0–t}, 103% for AUC_{0–∞}, and 94% for C_{max}. 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 t_{max}.However, if we administer the same doses, elimination should be prolonged to a similar extent (CL

_{T2}≈ CL_{T1}).Hence, GMR estimates for all PK metrics would be unbiased (≈90%)

^{4}reflecting the true relative BA.- I’ve heard rumors that in MENA states the originator is preferred by
*some*assessors. If possible, opt for a scientific advice.

- It was an intermediate strength and strict dose-proportionality was already established.

- 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.

- Due to F
_{T2}< F_{T1}(less drug in the circulation after T_{2}) we challenge the enzyme less than with 2×T_{1}. Hence, the estimates might be slightly*higher*than 90%.

—

Helmut Schütz

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*Dif-tor heh smusma*🖖🏼 Довге життя Україна!_{}Helmut Schütz

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### Complete thread:

- Choice of comparator Mikkabel 2018-01-23 17:29 [Design Issues]
- Line extension Helmut 2018-01-23 17:40
- Proportionality and regression mittyri 2018-01-23 18:30
- Proportionality and regression Helmut 2018-01-23 18:41

- Line extension Mikkabel 2018-01-24 10:17
- Type II variationHelmut 2018-01-24 11:56

- Proportionality and regression mittyri 2018-01-23 18:30

- Line extension Helmut 2018-01-23 17:40