Beholder
★

Russia,
2019-11-13 12:47
(920 d 20:55 ago)

Posting: # 20798
Views: 5,566

## Reference drugs for triple combination test drug in Russia [Design Issues]

Hi to all!

Question mostly for Russian members of the forum but anybody who has smth to add is really welcomed.

There is such a situation: a triple combination (3 molecules in one tablet) will be studied in BE study. As reference drugs we can choose two options:

1. a combination of three separate single drugs (i.e. 3 separate tablets) i.e. 3 tablets
2. a combination of one FDC (2 molecules in one tablet) and a single drug (1 molecule in one tablet), i.e. 2 tablets. All of these drugs are reference drugs according to the GRLS system.

What is your opinion which option to choose?

Best regards
Beholder
PharmCat
★

Russia,
2019-11-13 21:25
(920 d 12:17 ago)

@ Beholder
Posting: # 20801
Views: 4,478

## Reference drugs for triple combination test drug in Russia

» i.e. 2 tablets. All of these drugs are reference drugs according to the GRLS system.
»
» What is your opinion which option to choose?

Hello!

Strictly for bioequivalence you should chose drug from register that have label "Reference drug". If no such drug - you should make
efficacy trial.

I heard there was a case when drug was registered in EU and BE in Russia was performed with separate reference drugs - but now this case is not approvable, but some companies try to do this.

If say strict - both cases is wrong.
Yura
★

Belarus,
2019-11-14 09:24
(920 d 00:18 ago)

@ PharmCat
Posting: # 20802
Views: 4,564

## Reference drugs for triple combination test drug in Russia

Hi everyone
I propose to consider the design 3х3х6 (combination versus three mono and combination versus small combination and mono)
Beholder
★

Russia,
2019-11-14 10:55
(919 d 22:47 ago)

@ Yura
Posting: # 20804
Views: 4,422

## Reference drugs for triple combination test drug in Russia

Hi Yura!

» I propose to consider the design 3х3х6 (combination versus three mono and combination versus small combination and mono)

Would like to conduct study in economic way without unsuficient studies performed.

Best regards
Beholder
Beholder
★

Russia,
2019-11-14 10:51
(919 d 22:52 ago)

@ PharmCat
Posting: # 20803
Views: 4,377

## Reference drugs for triple combination test drug in Russia

Hi PharmCat!

» Strictly for bioequivalence you should chose drug from

Yes, all above mentioned drugs are marked as reference drugs according to the register, i.e. three monodrugs from option 1 and FDC+monodrug from option 2.

» If say strict - both cases is wrong.

Why second is wrong? I have just found quite fresh and approved study with similar situation regarding reference drugs.

Best regards
Beholder
Mikalai
★

Belarus,
2019-11-15 13:36
(918 d 20:06 ago)

@ Beholder
Posting: # 20805
Views: 4,371

## Reference drugs for triple combination test drug in Russia

Hi Beholder,
The best approach is to speak with the regulator. We are discussing polypills which, in my opinion, should be registered for the first time after phase trials as reference drugs not after BE ones. The BE trials can be conducted when regulators have access to full dossiers of the reference drugs. The question is whether there is a reference drug with the three APIs in one tablet? If yes, then just proceed with a BE trial, if not then it is better to speak with the regulator. I know that in Russia as well as in Belarus very questionable products can be registered based on very questionable approaches. Also, there is a question about whether the sponsor plans to market the drug abroad?
Best regards,
Helmut
★★★

Vienna, Austria,
2019-11-15 13:45
(918 d 19:58 ago)

@ Mikalai
Posting: # 20806
Views: 4,315

## OT: Speak with the regulator

Hi Mikalai,

» The best approach is to speak with the regulator.

As I have heard from colleagues „speaking with Russian regulators” in an official setting is wishful thinking. An informal dinner might be the best one can get.

Dif-tor heh smusma 🖖
Helmut Schütz

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

Russia,
2019-11-15 20:07
(918 d 13:35 ago)

@ Beholder
Posting: # 20809
Views: 4,335

## Reference drugs for triple combination test drug in Russia

» Hi PharmCat!

»
» Why second is wrong?

If you look at federal law, you can find:

generic drug - a drug that has the same qualitative composition and quantitative composition of active substances in the same dosage form as the reference drug, and whose bioequivalence or therapeutic equivalence is confirmed by the reference drug with relevant studies.

That why I said "strictly", triple FDC can be compared with similar registered triple FDC.

Anyway can be some exceptions when this rule not work. May be it can be orphan drugs or some individual cases or regulatory abuse.

You mention clinical trial with HIV drug and 280 subjects in 2 sites - may be this is exception.

In general case you can do BE vs equal FDS or therapeutic equivalence.
mittyri
★★

Russia,
2019-11-15 23:29
(918 d 10:13 ago)

@ PharmCat
Posting: # 20811
Views: 4,328

## Reference drugs for triple combination test drug in Russia

Hi PharmCat!

» Anyway can be some exceptions when this rule not work. May be it can be orphan drugs or some individual cases or regulatory abuse.
"The exception that proves the rule"
Just what I have found in GRLS and that drugs were approved within a BE study against 2 Reference drugs
Amlodipine + Indapamide + Perindopril
Losartan + Amlodipine + Rosuvastatin
Indapamide + Rosuvastatin + Perindopril
(could be more, lazy to search)

I would not name it 'orphan' or 'individual'
Generic companies did develop almost all attractive double combinations for cardiovasulcar diseases and were trying to expand to triple combinations.

Kind regards,
Mittyri
PharmCat
★

Russia,
2019-11-16 17:22
(917 d 16:21 ago)

@ mittyri
Posting: # 20812
Views: 4,281

## Reference drugs for triple combination test drug in Russia

» Generic companies did develop almost all attractive double combinations for cardiovasulcar diseases and were trying to expand to triple combinations.

And all this at the moment is a offense against the law.
Beholder
★

Russia,
2019-11-18 10:13
(915 d 23:29 ago)

@ PharmCat
Posting: # 20819
Views: 4,221

## Reference drugs for triple combination test drug in Russia

» If you look at federal law, you can find:
» generic drug - a drug that has the same qualitative composition and quantitative composition of active substances in the same dosage form as the reference drug, and whose bioequivalence or therapeutic equivalence is confirmed by the reference drug with relevant studies.

PharmCat, if we take triple combination e.g. Losartan 100 mg/Amlodipine 5 mg/Rosuvastatin 20 mg (mittyris real example) and following reference drugs Losartan 100 mg/Amlodipine 5 mg and Rosuvastatin 20 mg than still the compared drugs have the same qualitative composition and quantitative composition of active substances in the same dosage form as the reference drug as you said. it is still losartan 100 mg whenever you take it.

Best regards
Beholder
PharmCat
★

Russia,
2019-11-18 22:47
(915 d 10:55 ago)

@ Beholder
Posting: # 20825
Views: 4,195

## Reference drugs for triple combination test drug in Russia

» PharmCat, if we take triple combination e.g. Losartan 100 mg/Amlodipine 5 mg/Rosuvastatin 20 mg (mittyris real example) and following reference drugs Losartan 100 mg/Amlodipine 5 mg and Rosuvastatin 20 mg than still the compared drugs have the same qualitative composition and quantitative composition of active substances in the same dosage form as the reference drug as you said. it is still losartan 100 mg whenever you take it.

Sorry, but no. Ask how FDC registration performs in EU or FDA. Russian regulatory doesn't have guidance about FDC, but it coming as EEU document. ... in the same dosage form as the reference drug(not drugs). No such reference drug: Losartan+Amlodipine+Rosuvastatin, there are two drug: Losartan+Amlodipine and Rosuvastatin. We don't know nothing about new FDC - no safety, no efficacy data. This is new drug.

look here.

We are talking about scenario 1: new FDC-FPP contains the same actives in the same doses as an existing FDC-FPP; that is it is a “generic” of the existing FDC-FPP

existing examples do not confirm the fact - is it legal or not.
mittyri
★★

Russia,
2019-11-19 09:25
(915 d 00:17 ago)

@ PharmCat
Posting: # 20826
Views: 4,314

## WHO FDC Scenario 2

Hi PharmCat,

» Sorry, but no. Ask how FDC registration performs in EU or FDA.

We all know that Russian practice does not follow EMA or FDA completely ('a very special way'). So we cannot link to that jurisdictions directly.

» Russian regulatory doesn't have guidance about FDC, but it coming as EEU document.

Do you have any links to the upcoming drafts or some mentions?

» We don't know nothing about new FDC - no safety, no efficacy data. This is new drug.

Yes, that's a new drug, but please look at the Scenario 2 from the link you provided
Scenario 2 The new FDC-FPP contains the same actives in the
same doses as an established regime of single entity products, and
the dosage regimen is the same. Alternatively the established
regime may involve combinations of single entities and FDCs, for
example, a single entity FPP combined with an FDC-FPP that
contains two actives. In all cases, the established regime has a
well-characterized safety and efficacy profile, and all of the FPPs
used in obtaining clinical evidence have been shown to be of good
quality.

The requirements for Scenario 2 are very similar to Scenario 1

» existing examples do not confirm the fact - is it legal or not.

Do you really think that registered FDC combinations are illegal?

Kind regards,
Mittyri
PharmCat
★

Russia,
2019-11-19 23:42
(914 d 10:01 ago)

@ mittyri
Posting: # 20831
Views: 4,299

## WHO FDC Scenario 2

» We all know that Russian practice does not follow EMA or FDA completely ('a very special way'). So we cannot link to that jurisdictions directly.

But we know that sometimes "FGBU" using EMA/FDA guidelines in expertise.

» Do you have any links to the upcoming drafts or some mentions?

Here

» Yes, that's a new drug, but please look at the Scenario 2 from the link you provided

So, if this new drug, hence not a generic, hence no bioequivalence as a registration trial.

» Do you really think that registered FDC combinations are illegal?

Why I can't really think that some drugs was registered illegal or with abusing? I saw successful bioequivalence trial of atorvastatin with 18 volunteers. But I can't recommend to do this even if a precedent exists (was exists).

It should be understood that for such drugs (even if it was possible to justify bioequivalence) at the time of re-registration all the missing data (efficacy, safety) may be requested as for the reference drug. Some companies take risks and make "force" registration in the hope of managing to get enough profit during this period.
mittyri
★★

Russia,
2019-11-20 11:32
(913 d 22:11 ago)

@ PharmCat
Posting: # 20836
Views: 4,166

## EEU FDC Scenario 5.3.2

Hi Pharmcat,

» But we know that sometimes "FGBU" using EMA/FDA guidelines in expertise.

Sometimes yes, sometimes not. Do you know what are the requirements for the registration of generic MR products? Do you know what are the differences with EMA/FDA? I can assure you, experts also know that.

» » Do you have any links to the upcoming drafts or some mentions?
» Here

OK, that document links to this one
The discussed FDCs are explained as a scenario 5.3.2
point 56 says that bridging studies are required comparing FDC with concomitant monodrugs administration along the bioequivalence justification
So we see in this scenario that PD studies are not required (till the moment the Sponsor wants to change some dosage or regimen), PK studies are going ALONG the bioequivalence study, so it could be done in one stage.
Tricky moment is clinical justification (p.57-58), but if the scientific evidence is good enough (tons of links), I don't think there could be a problem. If and only if there are no clinical studies performed before using such a combination, additional clinical studies should be requested. In other situations it is possible if the expert decides that there's not enough data explaining efficacy/safety, benefit/risk ratio.

» So, if this new drug, hence not a generic, hence no bioequivalence as a registration trial.

Generic is also a new drug since only the API is the same
That's why the law admits simplified procedure in such cases.

» Why I can't really think that some drugs was registered illegal or with abusing? I saw successful bioequivalence trial of atorvastatin with 18 volunteers.

That's a drawback of our expertise/inspection system and it is not related to the current topic. All BEQ studies required for registration could be performed within a high quality standard.
Even with EEU I showed that the criteria could be met with BEQ study(ies) only when the clinical data is available.

» It should be understood that for such drugs (even if it was possible to justify bioequivalence) at the time of re-registration all the missing data (efficacy, safety) may be requested as for the reference drug.

Yes, it could be requested if they are not presented in dossier. Tricky point is the data privacy - does that Sponsor have rights to use that clinical data? Are they copyrighted?
You know current state of affair: to stimulate the market the authorities in Russia admit the usage of clinical data in dossier of other Sponsors.
Is that a crime? Russian courts mainly say no.

Kind regards,
Mittyri
PharmCat
★

Russia,
2019-11-20 15:39
(913 d 18:03 ago)

(edited by PharmCat on 2019-11-20 15:56)
@ mittyri
Posting: # 20841
Views: 4,098

## EEU FDC Scenario 5.3.2

» The discussed FDCs are explained as a scenario 5.3.2
» point 56 says that bridging studies are required comparing FDC with concomitant monodrugs administration along the bioequivalence justification

If we continue, in paragraph 57 we find: it is necessary to provide documentation on the clinical use of the appropriate drugs in combination or through clinical trials, or published literature, or a combination of both. These data should argue the basis for the combined use of active substances. To establish a positive benefit-risk combination, it is not enough to exclusively provide data on the combined use of single-component drugs.

When you submitting a dossier you should indicate is it a reference drug or generic. It your drug is generic - you should find reference drug (single drug) - scenario 1. It you indicate yours drug as reference and want to do only one bioequivalnce trial you should provide data of using in combination and interaction ets., some time it can be done when FDC already registered in other regulations. Usually not enough to perform only BE study.

And than, "If say strict - both cases is wrong." - scenarion 1.

If new FDC have registration history and completely safety and efficacy data - it can be very individual case and make certain recommendations without a clear understanding also can be not correct.

» Is that a crime? Russian courts mainly say no.

It is a gray zone I think. FDC registration procedure is a gray zone also. And if the sponsor approaches responsibly to high-quality development - the sponsor will not use the gray zone of legislation.
mittyri
★★

Russia,
2019-11-21 12:38
(912 d 21:04 ago)

@ PharmCat
Posting: # 20851
Views: 4,052

## EMA example

Hi Pharmcat,

» If we continue, in paragraph 57 we find: it is necessary to provide documentation on the clinical use of the appropriate drugs in combination or through clinical trials, or published literature, or a combination of both. These data should argue the basis for the combined use of active substances. To establish a positive benefit-risk combination, it is not enough to exclusively provide data on the combined use of single-component drugs.

Please cite from the beginning: As noted in chapters 5.3.1 and 5.3.3.
So that point explains different scenarios.

» When you submitting a dossier you should indicate is it a reference drug or generic. It your drug is generic - you should find reference drug (single drug) - scenario 1. It you indicate yours drug as reference and want to do only one bioequivalnce trial you should provide data of using in combination and interaction ets., some time it can be done when FDC already registered in other regulations. Usually not enough to perform only BE study.

From your logic scenario 5.3.2 does not exist in principle You pointed that doc by your self.

» And than, "If say strict - both cases is wrong." - scenarion 1.

That's your point of view only and it is not supported by any docs or examples in Russia. As Beholder noticed above, the statement for generic drug in law could be interpreted more broader (as our experts do)

» If new FDC have registration history and completely safety and efficacy data - it can be very individual case

Is that example from EMA jurisdiction also an 'individual case'?

» FDC registration procedure is a gray zone also. And if the sponsor approaches responsibly to high-quality development - the sponsor will not use the gray zone of legislation.

Nothing grey here, just follow the common sense and real practice. If the sponsor has the Legal Clinical data from not fixed combination and performed BEQ studies - that's enough, not only in Russia as I showed above.

Kind regards,
Mittyri
Beholder
★

Russia,
2019-11-19 14:39
(914 d 19:04 ago)

@ PharmCat
Posting: # 20828
Views: 4,161

## Reference drugs for triple combination test drug in Russia

» We don't know nothing about new FDC - no safety, no efficacy data. This is new drug.

Why no safety and efficacy data!? Lets take abovementioned examples:

Amlodipine + Indapamide + Perindopril - here
Losartan + Amlodipine + Rosuvastatin - here.
Indapamide + Rosuvastatin + Perindopril here.

So, can we say that "In all cases, the established regime has a well-characterized safety and efficacy profile..." and proceed with Scenario 2 comparing triple combination with two reference drugs?!

Best regards
Beholder
Yura
★

Belarus,
2019-11-19 21:51
(914 d 11:51 ago)

(edited by mittyri on 2019-11-19 22:50)
@ Beholder
Posting: # 20830
Views: 4,131

## Reference drugs for triple combination test drug in Russia

Hi Beholder,
There is no reason for the regulator not to want to check section 4.5 of the Guideline on clinical development of fixed combination medicinal products :|>
Kind regards,
Yura

Edit: Guideline linked. Also changed the name in signature to the usual one[Mittyri]
PharmCat
★

Russia,
2019-11-21 14:02
(912 d 19:41 ago)

@ Yura
Posting: # 20853
Views: 4,029

## Reference drugs for triple combination test drug in Russia

Сomprehensive article:

doi:https://doi.org/10.30895/1991-2919-2019-9-1-14-27

Over the past 10 years some new fixed combinations containing previously registered drugs were approved for use in the Russian Federation based on the results of a single clinical study of bioequivalence in healthy volunteers versus registered monocomponent reference drug. However, this practice does not fully comply with current Russian legislation.

A. V. Dobrovolskiy - Scientific Centre for Expert Evaluation of Medicinal Products ("FGBU")