Type II variation [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2018-01-24 12:56 (2340 d 11:23 ago) – Posting: # 18287
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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, …).An example:
DT1 1 (F 100%) ▬▬, DT2 2 (F 90%) ▬▬, and at the high dose elimination is prolonged by ~12% due to saturation.


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).


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%.

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