Switching in theory & practice [General Sta­tis­tics]

posted by Helmut Homepage – Vienna, Austria, 2015-02-27 16:37 (2297 d 23:32 ago) – Posting: # 14513
Views: 7,173

Hi Kaushik,

» How do we tackle/address these issues, Is it relevant to evaluate the generic to generic switchability impact, as none of the guidelines talk about these, Is there any specific method to explore this issue of switchability impact considering the fact that the markets are getting flooded with "N" number of generics

Good question.

» I have seen methods such as Indirect Treatment comparision/Network meta analysis published in the literature …

I guess you are talking about Arne Ring’s paper?1 Interesting ideas. Robert Schall is one of the pioneers of PBE/IBE. See their Fig.1:

[image]


The common approach is A). Note that the arrows are bidirectional. In approval BE is established for T1,…,N R but not the other way ’round. This is not a problem in ABE because we could re­verse the procedure. There might be already a problem with reference-scaled ABE. If the vari­ances of T and R are not equal the decision is not reversible any more.

In B) substitute the tests by major variations of the reference (each supported by a BE study with the previous product). The WHO faced serious problems identifying reference products which were as close as possible to the formulation used in phase III. Another obstacle: The first generic might be tested to an “old” reference and later ones to newer ones.
Heretic question I : Would be R3 bioequivalent to R0?
Heretic question II: How many minor variations (supported by in vitro data) can one expect until the re­fe­rence would be no more bioequivalent to the original product?

In clinical practice we face something beyond A):

[image]


Only the blue comparisons were performed (BE established) but the red switches might take place as well. With four generics we have four established BEs but six potential switches which were never tested for ABE. With ten generics we have 45 and with twenty an amazing 190. A lesson in com­bi­na­torics.

» … and being used for this by Canadian FDA/EMEA

Surprises me. Do you have a reference?

» […] what's your opinion
» 1. on assesing the impact of generic to generic switchability by a statistical method

IBE would help in theory.

» 2. As a researcher is there any way out to statistically evaluate these growing number of generics getting flooded in the market

If we leave IBE aside I don’t think so. Or should generic #21 perform 21 ABE studies (against R and T1,…,20)? Although from a theoretical perspective switching is not covered by ABE there seem to be no major problems – unless we talk about NTIDs, where switching is not acceptable in some regulations (e.g., in Denmark) or not recommended by medical specialists.

See another interesting paper.2 From the conclusions:

Two generic products (T1 and T2) can be switched from one to another when the T1/R and T2/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T1–R and T2–R was conducted using a relatively large number of subjects.



    References:
  1. Ring A, Morris TBS, Hohl K, Schall R. Indirect bioequivalence assessment using network meta-analyses. Eur J Clin Pharmacol. 2014;70(8):947–55. doi 10.1007/s00228-014-1691-0
  2. Karalis V, Bialer M, Macheras P. Quantitative assessment of the switchability of generic products Eur J Pharm Sci. 2013;50:476–83. doi 10.1016/j.ejps.2013.08.023

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