## Houston, we have a problem! [RSABE / ABEL]

Dear Osama,

» Thank you for the brilliant explanation.

You are welcome! In the meantime I added more stuff to my post.
If my interpretation of the GL is correct (is it?) and applied as such by members of the GCC, we have a problem if the CVwR observed in the study is ≤30%.

What could be done?
• Regulatory side
• If high variability is suspected by the applicant, allow pre-specified wider limits for Cmax irrespective of the observed CV – like currently in South Africa and acceptable by the EMEA prior to 2006.1 Does not even require a replicate design.
• Implement ABEL instead. In line not only with the EMA but many other jurisdictions (the WHO, ASEAN States, Australia, Brazil, Canada, Chile, the East African Community, Egypt, the Eurasian Economic Union, New Zealand, the Russian Federation). A step towards glo­bal harmonization. Lower inflation of the type I error if CVwR ≤30% than with the current approach. However, inflation of the TIE also if CVwR >30% (up to ~45%), whereas there is none in the current approach. Many publications dealing with the issue; iteratively adjusting α is provided by PowerTOST’s function scABEL.ad(). Sample size estimation to compensate for the potential loss of power is provided by the function sampleN.scABEL.ad().
• Implementing RSABE (USA, China) would be no good idea. Nasty inflation of the TIE if CVwR <30% as well…
• Applicant’s side
• Ask the authority whether ABEL is an acceptable alternative to the current approach. Is it already?
• If not, adjust α with my -script. Be aware of the potential loss in power!
Maybe (‼) I will implement it in scABEL.ad() and sampleN.scABEL.ad(). No promises.
Edit: See this post.
• Utopia
• Within the last ten years many replicate studies were performed. Hence, we simply know a good number of drugs / drug products which are highly variable and pose no safety concerns. Sometimes entire classes of drugs are highly variable (e.g., proton-pump inhi­bi­tors). Agencies could simply recommend widened limits in product-specific guidelines. No clinical justification2 needed by applicants, no replicate design needed, no issues with inflation of the TIE. Sigh.

1. In the EU lots of accepted studies with 75.00–133.33%. Prior to 2001 limits of 70–143% were not uncommon for Cmax. Sometimes even for AUC…
2. An often overlooked detail. Regularly difficult to provide for generic companies with no access to the originator’s data. Generally just a lot of in the protocol.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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