Ohlbe
★★★

France,
2017-06-12 13:29

Posting: # 17488
Views: 4,713

## WHO: scaling for AUC ? [RSABE / ABEL]

Dear all,

The WHO is apparently opening a pilot phase to allow scaling for AUC on a case-by-case basis. Protocols and justifications are to be submitted in advance to the WHO PQP team.

Regards
Ohlbe
Helmut
★★★

Vienna, Austria,
2017-06-12 23:31

@ Ohlbe
Posting: # 17490
Views: 4,119

## WHO: Chapeau!

Dear Ohlbe,

» The WHO is apparently opening a pilot phase to allow scaling for AUC on a case-by-case basis. Protocols and justifications are to be submitted in advance to the WHO PQP team.

THX at lot for this gem! Obviously people at the WHO are more clever than the EMA’s – by avoiding this IMHO, undesired – side effect. Kudos!

Something puzzles me when reading the respective section of TRS 992, Annex 7, Section 7.9.3 “Highly variable active pharmaceutical ingredients” again…

A “highly variable API” has been defined as an API with an intrasubject variability of > 30% in terms of the ANOVA-CV (14). Proving the bioequivalence of FPPs containing highly variable APIs can be problematic because the higher the ANOVA-CV, the wider the 90% confidence interval. Thus large numbers of subjects must be enrolled in studies involving highly variable APIs to achieve adequate statistical power.
Although there is variability in how regulatory authorities deal with the issue of highly variable APIs, the most rigorous of the current approaches involve the scaling of bioequivalence acceptance criteria based on the intrasubject standard deviation observed in the relevant parameters for the comparator product (15–17). Of the two most common assessment parameters Cmax is subject to the highest variability and hence is the parameter for which a modified approach is most needed.
For highly variable FPPs it is recommended that a three-way partial replicate (where the comparator product is administered twice) or a four-way fully replicated cross-over bioequivalence study be conducted and reference-scaled average bioequivalence be employed to widen the acceptance interval for the Cmax parameter, if the intrasubject variability for Cmax following replicate administrations of the comparator product is > 30%. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84–143.19%. The applicant should justify that the calculated intrasubject variability is a reliable estimate and that it is not the result of outliers.

Translation of the WHO’s terms: highly variable API = highly variable drug (HVD), highly variable finished pharmaceutical product (FPP) = highly variable drug product (HVDP).
Neither in (14) nor in any of all the other Bio-International conference I attended, 30% was set as the limit for the API. The respective section of (14) reads:

In some cases, however, it has been difficult to meet these criteria in experiments with a reasonable number of subjects. This may be, at least in part, a function of high intrasubject variability of the drug itself and/or the drug product. […]
Role of Variability of Reference Product-The panel does, however, believe that there may be some value in seriously considering the possibility of varying the confidence interval acceptance criteria in accordance with the intrasubject variability of the reference product and/or expanding bioequivalence intervals based on pharmacodynamic considerations.

(my emphases)
The distinction between HVDs (highly variable if administered IV or as a solution) and HVDPs (highly variable if administered as a pharmaceutical product) was first made by Midha a couple of years later. Whether we have to deal with a HVD or a HVDP is of academic interest only. If reference-scaling would be only acceptable for HVDs (highly variable APIs!) many HVDPs would fall through the cracks. Example: CVintra of IV diclofenac <10% but CVintra of enteric coated diclofenac ~40%. At last the last paragraph of the WHO’s GL talks about “highly variable FPPs”. Confused? So am I.

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
ElMaestro
★★★

Denmark,
2017-06-13 00:08

@ Helmut
Posting: # 17491
Views: 4,059

## WHO: Chapeau!

Hi Hötzi,

» THX at lot for this gem! Obviously people at the WHO are more clever than the EMA’s

In actuality, they are for many practical purposes exactly the same people.

» Confused? So am I.

There is no point is asking why, I think. They need 4 periods? They specifically seem to want to compare variability for Ref and Test. Are we back to the all the stuff that didn't work 10-20 years ago, population BE and individual BE and such. Obviously not the case. So it is anyones guess what the intent is given the wording.
However, there is plenty useful info in the guidance. Don't let a few inconsistencies spoil the party. Let the scaling for AUCt commence...

It of course comes at a handy time when WHO are opening up for biologics. This isn't a co-incidence .

I could be wrong, but...
Best regards,
ElMaestro
nobody
nothing

2017-06-13 09:28

@ ElMaestro
Posting: # 17492
Views: 4,019

## WHO: Chapeau!

» It of course comes at a handy time when WHO are opening up for biologics. This isn't a co-incidence .

Hi!

Didn't have a look at PARs, but EMA has a high number of biosimilars approved (compared to e.g. FDA), is the variability in AUC really an issue and how did the applicants account for, if EMA allows no scaling for AUC?

Kindest regards, nobody
Helmut
★★★

Vienna, Austria,
2019-06-10 11:23

@ ElMaestro
Posting: # 20322
Views: 265

## WHO: Chapeau!

Hi ElMaestro,

» » Obviously people at the WHO are more clever than the EMA’s

Update 22 November 2018:

As of November 2018, PQTm will accept the use of scaling of the AUC acceptance criteria for data from a full 4-period replicate design study for products containing albendazole or mebendazole. It is not necessary to provide a scientific justification a priori as described below for albendazole or mebendazole.

Only those two? No other HVD(P)s in the list of essential drugs? Or no studies submitted in the pilot phase since June 2017?

» They specifically seem to want to compare variability for Ref and Test.

Still no information how that should be done.
• Like in the days of PBE/IBE
• ‘Similar’ variability was concluded if $0.667\leq s_{wT}/s_{wR}\leq1.500$.
• Like in the FDA’s warfarin guidance
• Variabilities are considered ‘compar­able’ if the upper confidence limit of $\sigma_{wT}/\sigma_{wR}\leq2.5$.

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
ElMaestro
★★★

Denmark,
2019-06-11 18:51

@ Helmut
Posting: # 20323
Views: 183

## WHO: Chapeau!

Hi Hötzi,

» Only those two? No other HVD(P)s in the list of essential drugs?

Only waiver for the argumention for those two. For the rest you may still be able to scale but it requires lots and lots of .

I could be wrong, but...
Best regards,
ElMaestro
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