Bioequivalence and Bioavailability Forum • Article: BE-criteria too strict sometimes?

Helmut
★★★

Vienna, Austria,
2014-09-23 14:39
(3876 d 08:51 ago)

Posting: # 13558
Views: 16,746

Article: BE-criteria too strict sometimes? [BE/BA News]

Dear all,

just discovered an interesting paper. Below its abstract (and my emphases):

Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venturesome for different drugs. A PBPK model constructed with Simcyp Simulator^® using reported biopharmaceutics parameters for ibuprofen was coupled with two published PD models: one for antipyresis and one for dental pain relief. Using products with doses of 400 mg and 10 mg/kg as “reference (R)” drug products, virtual products with doses of 280 mg and 7 mg/kg, respectively, could be interpreted as representing bioinequivalent test (T) drug products, as the point estimate for the ratios T/R are well below the bioequivalence limits. Despite being bioinequivalent in terms of PK, these lower doses were shown to be therapeutically equivalent to the higher doses because of the flat dose–response relationship of ibuprofen. Sensitivity analysis of the PBPK/PD models demonstrated that gastric emptying time, dissolution rate and small intestine pH are variables that influence ibuprofen PK, but do not seem to significantly affect its PD. It was concluded that current bioequivalent guidance might be unnecessarily restrictive for ibuprofen products.

Cristofoletti R, Dressman JB. Use of Physiologically Based Pharmacokinetic Models Coupled with Pharmacodynamic Models to Assess the Clinical Relevance of Current Bioequivalence Criteria for Generic Drug Products Containing Ibuprofen. J Pharm Sci. 2014;103(10):3263–75. doi:10.1002/jps.24076.

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Ohlbe ★★★ France, 2014-09-24 00:20 (3875 d 23:09 ago) @ Helmut Posting: # 13560 Views: 14,624	Article: BE-criteria too strict sometimes? Post reply
	Dear Helmut, That's all very fine for efficacy. But what about safety ? — Regards Ohlbe

Helmut
★★★

Vienna, Austria,
2014-09-24 05:34
(3875 d 17:55 ago)

@ Ohlbe
Posting: # 13561
Views: 14,606

Risk assessment

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Hi Ohlbe,

❝ That's all very fine for efficacy. But what about safety ?

That’s not really covered in the paper since the authors explored only bioinequivalence at the lower end (T/R 70%) of 400 mg. However, higher IR strengths of 600, 650, and 800 mg (CR 1,000 mg) are on the European market; note that 400/0.7 < 600. Above 400 mg the PK is less than dose proportional. The maximum daily dose is 2,400 mg. In the Biowaiver Monograph the risk was assessed as being low.

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Ohlbe ★★★ France, 2014-09-24 12:22 (3875 d 11:07 ago) @ Helmut Posting: # 13562 Views: 14,559	Risk assessment Post reply
	Dear Helmut, You're right. When I wrote my message I failed to consider that the drug is ibuprofen. But that would be something to keep in mind before attempting any extrapolation. Medicinal products are authorised based on benefit / risk, not just benefit. — Regards Ohlbe

nobody nothing 2014-09-30 19:59 (3869 d 03:30 ago) @ Ohlbe Posting: # 13623 Views: 14,329	Risk assessment Post reply
	Hmmm... do I get this right that biowaivers for ibuprofen are dead? Alvarez C1, Núñez I, Torrado JJ, Gordon J, Potthast H, García-Arieta A. Investigation on the possibility of biowaivers for ibuprofen. J Pharm Sci. 2011 Jun;100(6):2343-9. Epub 2011 Jan 14. doi: 10.1002/jps.22472. PMID: 21491448 ...see authors of paper and biowaver... — Kindest regards, nobody

Helmut
★★★

Vienna, Austria,
2014-10-01 15:02
(3868 d 08:27 ago)

@ nobody
Posting: # 13631
Views: 14,353

Risk assessment

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Ὀδυσσεύς

❝ ...see authors of paper and biowaver...

I’m ready to believe a lot Henrike writes. Do you have access to the paper? The abstract doesn’t state the strengths tested in those studies.

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nobody nothing 2014-10-01 15:32 (3868 d 07:57 ago) @ Helmut Posting: # 13633 Views: 14,310	Risk assessment Post reply
	Nope, and as the journal comes with DRM bush I'm not willing to pay a 25 bugs for this piece of information at that time... oh, wait, I can get it for 8,50 as a paper copy... Come back later! — Kindest regards, nobody

ElMaestro
★★★

Denmark,
2014-09-24 13:20
(3875 d 10:09 ago)

@ Helmut
Posting: # 13563
Views: 14,585

Are all men born equal?

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Hi Hötzi,

in the world of API's (and their receptors/targets) all men are not born equal. This paper might be a good illustration that one size does not necessarily fit all.
At the level of molecular pharmacology it is well illustrated by the fact that fits of effect versus concentration very often involves an empirical Hill constant that is specific to the effector at its given receptor. This is a constant that determines how steep or shallow a DRC is. By its nature it can well differ from efficacy to safety.

Fluticasone propionate or any corticosteroid for inhalation make good examples of drugs with a shallow efficacy dose-response curve, so there are almost no efficacy worries but safety is stil quite a concern.

I guess I am trying to say that yes I agree sometimes the 80.00-125.00 criterion appears too strict.

By the way, you and Ohlbe got it all wrong in your discussion of safety and benefit/risk. At EMA the decisions are not taken on basis of benefit/risk - decisions are taken only on basis of risk :-D

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felipeberlinski ☆ Brazil, 2014-09-24 20:47 (3875 d 02:42 ago) @ ElMaestro Posting: # 13569 Views: 14,584	Article: BE-criteria too strict sometimes? Post reply
	This article is interesting although the opposite would also be true? BE - criteria too wide sometimes? All drugs must be treated equally? I have already seen some discussion regarding NTI drugs and this can be the next challenge for the comming generics. It is to think about it

Helmut
★★★

Vienna, Austria,
2014-09-24 21:14
(3875 d 02:15 ago)

@ ElMaestro
Posting: # 13570
Views: 14,876

Some animals are more equal than others

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Hi ElMaestro,

❝ I guess I am trying to say that yes I agree sometimes the 80.00-125.00 criterion appears too strict.

Maybe. The origin of these limits lies in the dark ages. However, see these quotes from presentations given at the “1^st MENA Regulatory Conference on Bioequivalence, Biowaivers, Bioanalysis and Dissolution” (Amman, 23/24 September 2013):

“Bioequivalence based on the comparison of bioavailability under strict criteria has proved to be the gold standard for the approval of generic medicinal products with ca. 40 years of experience without major incidents.”¹
“No prospective study has ever found that an FDA approved generic product does not show the same clinical efficacy and safety as the innovator product, even when special populations (e.g., elderly, women, severely sick patients) are studied.”²

In other words, even if the concept might not be strictly scientific at all, it seems to “work”. There are some hints that the concept might be too strict (or the other way ’round, less stringent criteria would also serve the job):

Products entered the market approved by methods which nowadays would provoke only a smirk in any assessor’s face. Examples: FDA’s “75/75-rule”, testing for a significant difference, arbitrarily widening the acceptance range, studies in steady state only or based on a metabolite in order to reduce variability… Where are the failures?
The wide range from lousy study conduct up to plain fraud which slipped through the attention of regulators for years. Remember Ranbaxy? THX to GMP (which seems to be more easy to inspect than GCP) which results in acceptable product performance – even if bioinequivalence would be the “true” result.

Serious suggestions were made in the past to move forward.

At one of the BioInternational Conferences (Munich 1994) different limits for classes of drugs were discussed. But: Who would have the balls to set them?
Les Benet also suggested that as part of any NDA the innovator should run a large replicate study and release the CV_W to the public domain. That would have put an end on pilot studies in ANDAs estimating the variability (however, still necessary to get an idea about the GMR).
Reference-scaling for HVDPs is dependent on the CV_WR estimated in particular studies. That’s completely different from the “one size fits all” 80/125-concept. Sooner or later we will have generics of HVDPs on the market which were approved according to different rules.
Furthermore, reference-scaling is not reversible. In any 2-way cross-over we could switch the coding of T and R. Studies showing BE for T/R would also show “BE” for R/T. Since the products’ CV_w must not be identical (an assumption in 2,2,2-studies) – and in fully replicated designs we have all means to assess that* – a study which passes T/R in RSABE/ABEL based on CV_WR must not necessarily pass R/T based on CV_WT as well. Of course one can make an argument that such a comparison is futile, but I find it a little bit disturbing. At least it violates the symmetry required by the WHO: “The procedures should lead to a decision scheme which is symmetrical with respect to the two formulations (i.e. leading to the same decision whether the multisource formulation is compared to the comparator product or the comparator product to the multisource formulation).”
The two Lászlós suggested that regulators should collect CVs of reference products and pool the variances. Due to the much higher sample size such an estimate would be more accurate (and precise) than anything one estimates in an actual study. Then regulators should publish a product-specific acceptance range. As a nice side-effect it would end the inflation of the patient’s risk we face right now.

José A Guimarães Morais
EMA Perspectives on BE Regulations
Leslie Z Benet
Why Do Bioequivalence Studies in Healthy Volunteers?

For incomprehensible reasons EMA in their holy Q&A-document prefers to ignore the information which easily can be obtained in replicate studies. At the days of population-/individual-BE these designs were developed exactly for this reason: To assess different variabilities of test and reference (and the magic subject-by-formulation interaction). In following EMA’s “Methods A & B” we are forced to assume a common variance of T and R (like in 2,2,2-studies) and “Method C” – which would take the entire data-structure into account – is not declared to be “compatible with the CHMP guideline”. At the end our gurus made an interesting statement about “Method C”:
“This model […] will generally give wider confidence intervals
than those produced by methods A and B.”
Simply bizarre. Regulators suggesting a liberal/anticonservative method. Once one of them at a conference made a strong statement: “We are interested in public health, not the profit of the pharmaceutical industry.” I’m not so sure…

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Helmut Schütz

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nobody
nothing

2014-09-24 22:32
(3875 d 00:58 ago)

@ Helmut
Posting: # 13572
Views: 14,485

Some animals are more equal than others

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❝ At one of the BioInternational Conferences (Munich 1994) different limits for classes of drugs were discussed. But: Who would have the balls to set them?

Wow, that's long ago, but was a nice meeting, iirc :-D

Balls? Ask Leslie Z. B.? ;-)

In your dreams he recommends that the originator is doing the job for generics companies, that's having pretty much balls, in my opinion.

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Kindest regards, nobody

Lucas
★

Brazil,
2014-10-14 19:02
(3855 d 04:27 ago)

@ Helmut
Posting: # 13706
Views: 14,043

Some animals are more equal than others

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Hi everybody!

❝ Maybe. The origin of these limits lies in the dark ages.

❝ • Reference-scaling for HVDPs is dependent on the CV_WR estimated in particular studies. That’s completely different from the “one size fits all” 80/125-concept. Sooner or later we will have generics of HVDPs on the market which were approved according to different rules.

I would love to see studies showing that the 80-125% and also Reference-scaling are actually good. I'm not an expert in physiology, and maybe that's the problem, but I think that this is a very strong statement when you say that some drugs does not show difference in efficacy/safety when the 80-125% criteria is applied. Even worst may be for HVDPs. It is scientifically proved that higher the CV wider is the therapeutic index? Do all drugs, regardless of class or indication, have similar PBPK/PD relation?

Helmut
★★★

Vienna, Austria,
2014-10-14 23:15
(3855 d 00:14 ago)

@ Lucas
Posting: # 13707
Views: 14,265

Some animals are more equal than others

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Hi Lucas,

❝ ❝ The origin of these limits lies in the dark ages.

❝ ❝ • Reference-scaling for HVDPs is dependent on the CV_WR estimated in particular studies. That’s completely different from the “one size fits all” 80/125-concept. Sooner or later we will have generics of HVDPs on the market which were approved according to different rules.

❝

❝ I would love to see studies showing that the 80-125% and also Reference-scaling are actually good.

There were very few prospective studies where the null-hypothesis was inequivalence and the study’s primary endpoint was clinical effect. BE was secondary. As you can imagine these studies were quite large. Innovators tried to challenge the BE concept and loved to see was sumfink like: BE shown in the PK study, but not equivalent in effect(s). All studies failed to show that. At the end innovators gave up. The last one was performed at UCSF. The company tried to prevent the investigator from publishing the study. Was a big story.
See Les Benet: http://www.youtube.com/watch?v=UjgE39CUlSw (navigate to 35:49).

ABE was never developed as a scientific theory (construction and testing of falsifiable hypotheses). The ±20% entered the scene in an ad-hoc manner because there were serious problems in the late 1970 indeed and something had to be done – quick. If my house is on fire I’d rather not discuss whether the water pressure of the pump might be sufficient, etc. I want the fire brigade to act – now.
Retrospectively the ABE-concept seems to work. But since it was never seriously challenged the – arbitrary – 20% might be more restrictive than necessary for some drugs. Before reference-scaling we had in some regulations three dichotomous acceptance ranges: 90–111% (NTIDs), 80–125% (well), and 75–133%/70–143% (HVDPs).

❝ […] I think that this is a very strong statement when you say that some drugs does not show difference in efficacy/safety when the 80-125% criteria is applied.

Not sure whether I wrote that. Are you reading in between the lines? It would be worthwhile to go back in time when – apart from ABE – prescribability (by population BE) and switchability (by individual BE) was discussed. For PBE and IBE we need fully replicated designs because not only the GMR (which is accessible in a 2×2 cross-over) is compared, but also the variances. In PBE the total variance and in IBE the variances of T and R (+ the magic subject-by-formulation interaction).
The ideas was that – based on PBE – the physician could chose a product for a drug-naïve (!) patient and – based on IBE – patients could switch products while already under treatment. The entire concept went down the drain.
Strictly speaking ABE does not allow switching under therapy. But it happens all the time. In some countries the pharmacist has to switch to a generic even if the physician stated the innovator on the prescription. It would not make sense to switch between two generic NTIDs anyway. Even stated on Denmark’s website.

One option would be to run all BE studies in a full replicate design and scale according to the references CV. But then we would face alpha-inflation (as discussed somewhere else in the forum) and products which were approved to different rules. It’s very, very tricky.

❝ Even worst may be for HVDPs. It is scientifically proved that higher the CV wider is the therapeutic index? Do all drugs, regardless of class or indication, have similar PBPK/PD relation?

José used the word “proof” sloppily. We can’t prove anything in science. We can only make a statement like “All swans are white”. This is a working hypothesis awaiting rejection – which actually was done in 1790 when the first black swan was described. My personal working hypothesis “No swans are red” still holds.

Seriously: The statement “highly variable drugs are safe drugs” is observational, but well founded. The innovator explored the dose-response curve in development and if it would not be flat, there would have been efficacy/safety problems in phase III. If we have a steep dose-response curve high variability would lead to lacking efficacy or toxicity from day-to-day. If we are talking about generics it is even more clear. The innovator has a database of hundreds–thousands of patients before he gets the approval. If a generic comes in we have a database of millions of patient-years. In other words I would worry less about a RSABE-study of a generic than about a similar study of the innovator going from clinical batches to full production.

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Lucas
★

Brazil,
2014-10-15 00:25
(3854 d 23:05 ago)

@ Helmut
Posting: # 13708
Views: 14,096

Some animals are more equal than others

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Hello Helmut!

As always quite enlightening! Thx for the info about the history behind BE, it did not had reached Brazil just yet. Very good information is always welcome.

❝ Not sure whether I wrote that. Are you reading in between the lines?

No, not what I meant. I don't think that you've said that, I meant that the regulators and the creators of the approach stated that.

❝ It would be worthwhile to go back in time when – apart from ABE – prescribability (by population BE) and switchability (by individual BE) was discussed.

BTW Dr Laszlo Endrenyi gave us a lecture about that recently in a workshop organized by our company at ANVISA. He said many good things about you in our lunch/dinner breaks. :hungry:

❝ The innovator has a database of hundreds–thousands of patients before he gets the approval. If a generic comes in we have a database of millions of patient-years.

Do you think that we can assume that outside of EUROPE/USA/etc also? The reason I'm asking it is that it seems to me that in "3rd world countries" (or using the polite way to call countries like mine: developing countries) I'd not be sure about that, due to late developing of regulations (when compared to EU and US). :ponder:

Helmut
★★★

Vienna, Austria,
2014-10-15 05:20
(3854 d 18:10 ago)

@ Lucas
Posting: # 13710
Views: 14,069

Some animals are more equal than others

Post reply

Hi Lucas,

❝ ❝ It would be worthwhile to go back in time when – apart from ABE – prescribability (by population BE) and switchability (by individual BE) was discussed.

❝

❝ BTW Dr Laszlo Endrenyi gave us a lecture about that recently in a workshop organized by our company at ANVISA.

He is the perfect lecturer for this topic.

❝ He said many good things about you in our lunch/dinner breaks. :hungry:

Nice to hear. I like him very much and always enjoy meeting him. When he talks about new ideas he uses the word “enthusiastic” at an amazing frequency. His scintillating eyes show that inside he is younger than some members of the e-generation. He performed so much pioneering work and never is arrogant when he says “We have done that already 30 years ago”. What he means is: Don’t re-invent the wheel, let’s move forward to new frontiers!

❝ ❝ The innovator has a database of hundreds–thousands of patients before he gets the approval. If a generic comes in we have a database of millions of patient-years.

❝

❝ Do you think that we can assume that outside of EUROPE/USA/etc also?

Yes.

❝ The reason I'm asking it is that it seems to me that in "3rd world countries" (or using the polite way to call countries like mine: developing countries) I'd not be sure about that, due to late developing of regulations (when compared to EU and US). :ponder:

Drugs don’t care about regulations. It’s us who fail.
This image on the box was not a clever idea in countries with a high rate of illiteracy:
[image]

Is this one more clear?
[image]

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