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ElMaestro
Hero

Denmark,
2018-06-23 10:14

Posting: # 18950
Views: 1,012
 

 Potency correction - I still don't get it [Regulatives / Guidelines]

Hi all,

section 4.1.8 of the EMA guideline opens up for potency calculation for BE evaluation.
I can see what it does. I still can't, after having read up on this for 8 years, see in which way that opportunity does anything good for the sake of the EU patient.

Can somebody give me a numerical example illustrating why potency correction is to the advantage of not only the Sponsor but also the patient??
90% CI is 77-108, but if assays differ, then we divide and multiply and do some gymnastics on the numbers, and hey presto we now have an approvable product. Nice for Sponsor (or at least the guy in the Armani suit). But is that really advantageous for the Patient? It may be if we seriously play around with the definition of average bioequivalence. Let me hear your thoughts, please: Under which assumptions in your opinion will a potency correction help regulators decide on relative rate and extent of absorption, and how does this (these) assumption(s) fit into your understanding of average BE?

Many thanks.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
d_labes
Hero

Berlin, Germany,
2018-06-23 18:04

@ ElMaestro
Posting: # 18951
Views: 900
 

 Potency correction - Only in exceptional cases

Dear ElMaestro,

» section 4.1.8 of the EMA guideline opens up for potency calculation for BE evaluation.
» ...

read the Section again. It states unambigously:
"In bioequivalence studies, the pharmacokinetic parameters should in general not be adjusted for differences in assayed content of the test and reference batch."

That was the policy which my former company followed over years. Ended with the publication of the 2010 guideline.
This is indeed
» ... some gymnastics on the numbers, and hey presto we now have an approvable product. Nice for Sponsor (or at least the guy in the Armani suit).

But reading the next sentence:
"However, in exceptional cases where a reference batch with an assay content differing less than 5% from test product cannot be found (see section 4.1.2) content correction could be accepted ..."
Emphasis by me.

» I still can't [...] see in which way that opportunity does anything good for the sake of the EU patient.

Imagine for example there is no reference product of 50 µg content, no one produces the 50 µg formulation any longer, but only one with 60 µg. And the patient is optimally prescribed a dose of 50 µg. Having such a formulation with 50 µg is a benefit for the patient, I think.

Regards,

Detlew
ElMaestro
Hero

Denmark,
2018-06-23 19:55

@ d_labes
Posting: # 18952
Views: 885
 

 Potency correction - Only in exceptional cases

Dear d_labes,

» read the Section again.

Did many times, hence my question :-)

» Imagine for example there is no reference product of 50 µg content, no one produces the 50 µg formulation any longer, but only one with 60 µg. And the patient is optimally prescribed a dose of 50 µg. Having such a formulation with 50 µg is a benefit for the patient, I think.

That is an interesting aspect and not one that I ever came across. In EU this would qualify as a 10.3 and in the US as a 505(b)(2), but be that as it may.
Would your example really make T(50) bioequivalent to R(60) (after all you are saying T(50) is a better treatment option than R(60)), or would you just call T(50) approvable?

It makes for an interesting discussion, philosophically at least, when we use your example in conjunction with section 1.1: "Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits."
One one hand you can say you are definitely not testing the same molar dose (whether actual or by intention) so they can't be BE. On the other hand you can say the potency correction adjusts for exactly that discrepancy.

Anyhow, the intention with section 4.1.8, I think, was to pave the way forward for a case where e.g. the Test has a potency of 104% and the Ref has a potency of 95% of the (identical) label claim etc. I believe so due to the wording that mentions the difficulty of finding a matching reference batch (not a matching reference strength). As always I could be wrong. I hope others will chime in.:-)

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-06-24 00:55

@ ElMaestro
Posting: # 18954
Views: 865
 

 Potency correction: Rather why than when

Hi ElMaestro & all,

let’s consider the basics. We have a set of two equations
  1. AUCT = ƒT·DT/CLT
  2. AUCR = ƒR·DR/CLR
which consist of eight variables. We are interested to compare the bioavailabilities or ƒTR (not the individual values ƒT and ƒR), reducing the variables to seven. We have AUCT and AUCR. Can this set solved for ƒTR? Obviously not. We need two assumptions.
  1. CLT = CLR
  2. DT = DR
Only then we can cross them out in the set and walk away happily with ƒTR = AUCT/AUCR.

The first assumption is not that bad. Clearance is a property of the drug, not the formulation. If we face variability of inter-occasion clearances it increases the residual error. Nasty for HVDs but no big deal (increased sample size, patient’s risk not affected).

The second one is much more tricky. As you rightly stated BE by definition means administration of the same molar dose. Here trouble starts. Reference is made to the labeled content. OK, we try to find test and reference batches which are as close as possible. Stupid enough the analytical assay is not free of error.* That’s why nobody with a clear state of mind estimates the sample size with a T/R of 100% even if this comes out in the analyses. To complicate things for generics the method is only validated for the test product. You can only hope that it gives unbiased results for the reference as well. Asking the originator for a CoA is not option. Might be easy for a simple IR product but already difficult for some MR products and can get really nasty for creams and ointments…

Acc. to the Canadian guidances (1992) both analyses (original and adjusted for measured content) had to be presented. No idea what happened if a study passed one and failed the other. Acc. to the WHO’s draft (1995) it was possible to adjust if Δ >5% and stated in the protocol. Only one analysis decisive.
Let’s explore your example. CI 77–108% (say for true DT = DR = 100), combinations of Δ 5% (adjustment not allowed) or slightly above (closer batches can’t be found). The Δ is either split or entirely on one side. This gives:

 Δ    adj.   DT       DR       90% CI         
──────────────────────────────────────────────
0.00   no  100.00  100.00  77.00  108.00  fail
──────────────────────────────────────────────
5.00   no   97.50  102.50  77.00  108.00  fail
5.00   no  102.50   97.50  77.00  108.00  fail
5.00   no   95.00  100.00  77.00  108.00  fail
5.00   no  100.00  105.00  77.00  108.00  fail
5.00   no   95.00  100.00  77.00  108.00  fail
──────────────────────────────────────────────
5.01  yes   97.50  102.51  80.96  113.55  pass
5.01  yes  102.51   97.50  73.24  102.72  fail
5.01  yes   94.99  100.00  81.06  113.70  pass
5.01  yes  100.00  105.01  80.86  113.41  pass
5.01  yes   94.99  100.00  81.06  113.70  pass

If we adjust – with one exception – the test passes. When you ask for the relevance, that’s a philosophical question. I think that not adjusting is conservative. On the other hand, adjusting might be more realistic keeping assumption #2 in mind.
Of course, the 5% limit is arbitrary. Is there any upper limit? For most products the release-spec’s are ±10%. Then is would be possible to adjust for a 20% difference. That would match already Detlew’s example… Don’t know where to draw the line.


  • BTW, how representative is the mean of 6 or 12 units of a biobatch of 500,000? Content uniformity? Ha! When I started to explained the procedure “Take a blister, analyze 6 capsules,…” to a friend of mine (chemist in the cement industry) he interrupted me cause he was dying of laughter. Since the 1950s they have procedures to draw representative samples from a 5,000 tons batch. Start with about ~500 (!) from different locations, mixing, splitting, :blahblah: to end up with ~30. Books are written about that.
    From this perspective one could criticize biostudies in similar way (“Take a blister…”).

Cheers,
Helmut Schütz
[image]

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

Denmark,
2018-06-25 10:22

@ Helmut
Posting: # 18958
Views: 777
 

 Potency correction: Rather why than when

Hi Hötzi,

» let’s consider the basics. We have a set of two equations
  1. AUCT = ƒT·DT/CLT
    »
  2. AUCR = ƒR·DR/CLR
which consist of eight variables. We are interested to compare the bioavailabilities or ƒTR (not the individual values ƒT and ƒR), reducing the variables to seven.

You are on the right track. I think this was largely an answer to a question I didn't ask, and not answer to the question I asked. I believe I once again perhaps did not explain myself properly enough.

I will try and use your own language:
AUCT/AUCR=(fT/fR)(DT/DR)(CLR/CLT)
where we will assume CLT=CLR, so
AUCT/AUCR=(fT/fR)(DT/DR) or
(DR*AUCT) / (DT*AUCR) = fT/fR or

(DR/DT)*(AUCT/AUCR)=fT/fR

This multiplication by the dose ratio is essentially what the potency correction achieves. You can rearrange that also in another outright horrible fashion:

(AUCT/DT) / (AUCR/DR) = FT/FR

Ouch. Potency correction is the wonderful tool I can use to prove that 5x250 mg Schützomycin tablets are bioequivalent to 1x250 mg Schützomycin :-). Let us for the purpose of this discussion leave out non-linear kinetics etc.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-06-25 15:34

@ ElMaestro
Posting: # 18959
Views: 755
 

 Potency correction: Upper limit?

Hi ElMaestro,

» You are on the right track. I think this was largely an answer to a question I didn't ask, and not answer to the question I asked.

That’s the “thread-drift” phenomenon common to technical fora. There is always a smart ass giving explanations not asked for. If it happens often, possibly a troll.

» I believe I once again perhaps did not explain myself properly enough.

No, you did.

» You can rearrange that also in another outright horrible fashion:
» (AUCT/DT) / (AUCR/DR) = FT/FR
» Ouch. Potency correction is the wonderful tool I can use to prove that 5x250 mg Schützomycin tablets are bioequivalent to 1x250 mg Schützomycin :-).

Exactly. Same molar dose (in the BE definition) refers to the content stated in the label. Measuring actual content and giving the results already in the protocol is mandatory. The EMA and others decided that
  • If Δ ≤5% ⇒ assume that DT=DR (don’t adjust).
  • If Δ >5% ⇒ adjust for measured content (if no closer batches can be found).
Still the question is: Where to draw the line, i.e., what is the upper limit for an adjustment? I would say that a Δ of 400% is way too high (even for Schützomycin).
Of course, the GL uses an elastic clause (in exceptional cases […] content correction could be accepted.)

[image]Think about my example above. Release spec’s ±10%. The test is perfect (assayed content 100%).
You send a guy/doll on a trip to the member states of the EEA to buy batches of the reference. All are lousy (just passed the spec’s). Add assay error and you end up with Δ 12%. Nice justification (you tried really hard – not only three pharmacies in the neighborhood), stated in the protocol. Study passes after correction, but could be accepted.
You can’t be sure.

Cheers,
Helmut Schütz
[image]

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

Berlin, Germany,
2018-06-24 14:40

@ ElMaestro
Posting: # 18956
Views: 837
 

 Potency correction - Example

Dear ElMaestro,

as said in my post above the potency correction was abondoned in my company since 2010 so I couln't give a real example, but only a fictional.

Where I came across with potency correction last times was the case for OIPs.
Here the potency correction was applied based on the fine particle content of a distinct fraction of the fine particles, chosen based on correlation with the PK metrics.
IMHO this was really "gymnastics on numbers".

But at end of the day the sponsor is right.
And as far as I know the regulatory agency / agencies accepted that to a certain extent.

That example directs toward your opinion
» Anyhow, the intention with section 4.1.8, I think, was to pave the way forward for a case where e.g. the Test has a potency of 104% and the Ref has a potency of 95% of the (identical) label claim etc.

Regards,

Detlew
mittyri
Senior

Russia,
2018-06-23 22:53

@ ElMaestro
Posting: # 18953
Views: 882
 

 Potency correction - EAUnion opinion

Hi ElMaestro,

I don't have any experience of using that workaround and I bet noone has in Russia.
BTW I compared 'the gold standard' EMA Guideline and EAUnion Guideline.
(note that sections 4.1.2 and relevant in EAUnion GL are pretty similar)
EMA:
4.1.8 In bioequivalence studies, the pharmacokinetic parameters should in general not be adjusted for differences in assayed content of the test and reference batch. However, in exceptional cases where a reference batch with an assay content differing less than 5% from test product cannot be found (see section 4.1.2) content correction could be accepted.

EAUnion:
72 In bioequivalence studies, the pharmacokinetic parameters should in general not be adjusted for differences in assayed content of the test and reference batch. However, in exceptional cases where a reference batch with an assay content differs less than 5% from test product (in accordance with subsection 2 of current section) content correction could be accepted.
:confused::-D
Why bother? Just close that backdoor :cool:

Kind regards,
Mittyri
Ohlbe
Hero

France,
2018-06-25 10:10

@ ElMaestro
Posting: # 18957
Views: 788
 

 Potency correction - example

Dear El Maestro,

» I still can't, after having read up on this for 8 years, see in which way that opportunity does anything good for the sake of the EU patient.
» 90% CI is 77-108 [...]

Now let's take the opposite example: 90% CI is 81-110. Contents: 103% for T, 97% for R. Baseline correction and assay results pre-specified in the protocol. Outcome after correction: the study fails.

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2018-06-25 18:24

@ ElMaestro
Posting: # 18960
Views: 723
 

 Let me answer my own question

Thanks all,

Lots of good input in this thread.
Here's my own view. Bear in mind this was a question about assumptions.

In average BE we test if T and R on average do the same.
If we apply the potency correction to average BE then it will work if we are willing to test if if an average (or median or typical) batch of T and an average (or median or typical) batch of R R on average do the same, given that we may be dealing with an non-average (non-median, atypical) batch of R.
However, bear in mind the condition "where a reference batch with an assay content differing less than 5% from test product cannot be found" implies that the applicant is in no position to argue anything about the chosen batch being atypical, non-average, non-median. On top of that (4.1.2) "The Applicant should document how a representative batch of the reference product with regards to dissolution and assay content has been selected."

There you have the implied/implicit assumption (in bold above) for potency correction to work. And you have my opinion why it is a dead end until someone gives me a very good reason to think otherwise.
In this regard I will retain the privilege of defining what very good means. I do not have a protocol for it in which I can pre-specify it. :-)

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
d_labes
Hero

Berlin, Germany,
2018-06-25 19:49
(edited by d_labes on 2018-06-25 20:04)

@ ElMaestro
Posting: # 18962
Views: 707
 

 Someone, somebody - slightly OT

Dear ElMaestro!

» There you have the implied/implicit assumption (in bold above) for potency correction to work. And you have my opinion why it is a dead end until someone gives me a very good reason to think otherwise.

I'm not someone, somebody ... (in German "Jemand" or "Einer", both are guilty because they don't do what my wife request from me. "Jemand oder Einer müßte mal den Müll rausbringen" :cool:).

» In this regard I will retain the privilege of defining what very good means.

Thats your right acc. to the Habeas Corpus Act :-D.

» I do not have a protocol for it in which I can pre-specify it :-).

Thats a pitty. Because in other occasions you have wording covering all the bells and whistles of that philosophical questions :cool:.

Regards,

Detlew
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