ping4santosh
☆

India,
2020-03-06 09:21
(edited by ping4santosh on 2020-03-06 09:32)

Posting: # 21215
Views: 3,910

## Immediate release fixed dose combination product [Regulatives / Guidelines]

Hello Friends,

I am struggling with a project to find out the studies that we would require to register a fixed dose combination product in EU.

Basically we are trying to combine two different injections (One antibiotic and one antipyretic). Both the products are registered as individual API injection in EU. One product requires high pH for solubility and another is low pH. In order to combine these two that are stable at two different pH, we have added a stabilizer. Technically, it is feasible to combine both injections to make it one injection.

As we know, we don't need to do BA/BE study in case of Immediate release products to register the generic versions, can we extend the similar logic to a Fixed Dose Combination of two Immediate release products that are individually registered and we don't need to do any in-vivo studies?

Do we need to do any In-vivo study? If yes, what all do we need to do? Do we also need safety studies along with BA/BE? Do we need to do efficacy too?

Best regards
SKM
Ohlbe
★★★

France,
2020-03-06 10:35

@ ping4santosh
Posting: # 21217
Views: 2,214

## Immediate release fixed dose combination product

Dear SKM,

» I am struggling with a project to find out the studies that we would require to register a fixed dose combination product in EU.

First of all, if no product is registered yet with this FDC: you will have to demonstrate the rationale / therapeutic interest of combining the two active principles. Though patients who have an infection are usually also treated with an antipyretic, keeping the two separate gives more flexibility to choose the antipyretic and to adjust the dose and the dosing frequency. Also, having an injectable antipyretic combined only makes sense in patients who cannot swallow an oral formulation. Antipyretics in FDC increase the risk of overdose from different sources. FDCs are seen as improving the quality of life of patients and treatment observance by reducing the number of pills to swallow, but in the case of injectables it depends on the injection route. If IV route and the patients have a perfusion anyway, it makes no difference to them.

Reading EMA's Guideline on clinical development of fixed combination medicinal products, I don't see much chances of registration of this combination in the EU. To quote the guideline:
Applicants are required to justify the pharmacological and medical rationale for the particular combination of active substances within the fixed combination medicinal product and for the intended therapeutic indication. The rationale should also account for the posology, including dosing frequency and dosing schedule of the active substances included in the fixed combination medicinal product. Part of the rationale for fixed combination medicinal products may be to optimise the use of the medicine in terms of (number of) doses administered and patient adherence, or to help prescribers optimise and/or implement treatment where use of multiple active substances is indicated. Such simplification of therapy is, however, insufficient by itself for a complete justification of a fixed combination medicinal product.

» Do we need to do any In-vivo study? If yes, what all do we need to do? Do we also need safety studies along with BA/BE? Do we need to do efficacy too?

Well, I think more information is needed here. What is the injection route precisely, IM, IV, SC ? Is this a solution or a suspension at your pH ? Are the excipients (including your stabiliser) well known and in common use ? Are they known to potentially cause adverse events ?

Regards
Ohlbe
ping4santosh
☆

India,
2020-03-09 11:50

@ Ohlbe
Posting: # 21226
Views: 2,153

## Immediate release fixed dose combination product

Dear Ohlbe,

Many thanks for your detailed reply. Unfortunately, I'm bound by confidentiality clause. Hence my responses are guarded. Please find my responses below:

» First of all, if no product is registered yet with this FDC: you will have to demonstrate the rationale / therapeutic interest of combining the two active principles. Though patients who have an infection are usually also treated with an antipyretic, keeping the two separate gives more flexibility to choose the antipyretic and to adjust the dose and the dosing frequency. Also, having an injectable antipyretic combined only makes sense in patients who cannot swallow an oral formulation. Antipyretics in FDC increase the risk of overdose from different sources. FDCs are seen as improving the quality of life of patients and treatment observance by reducing the number of pills to swallow, but in the case of injectables it depends on the injection route. If IV route and the patients have a perfusion anyway, it makes no difference to them.

The FDC has potential as both the product are single dose treatment with comparable pharmacokinetics. Hence, the possibility of overdose is minimal. There won't be any potentiating effect of the products on each other but of course it will save an additional prick. Its I/M or S/C route of administration. So the benefit from perfusion can't be leveraged.

» Reading EMA's Guideline on clinical development of fixed combination medicinal products, I don't see much chances of registration of this combination in the EU. […]

Thanks for sharing the guideline. I will go through it. The dosing frequency for both the product is just one time treatment. This is the reason of our interest. When we have both the product similar in it's posology, why do we need two pricks? Won't it suffice as the rationale of FDC?

» » Do we need to do any In-vivo study? If yes, what all do we need to do? Do we also need safety studies along with BA/BE? Do we need to do efficacy too?
»
» Well, I think more information is needed here. What is the injection route precisely, IM, IV, SC ? Is this a solution or a suspension at your pH ?

Can you kindly let me know the paths to be followed for both suspension and solution?

» Are the excipients (including your stabiliser) well known and in common use ? Are they known to potentially cause adverse events ?

I'm not sure. Can you let me know the path to be followed for both possible scenarios? Well known stabilizer and new stabilizer?

Thanks a ton.
SKM

Merged:
Lets consider it as a solution with well established excipients without any known adverse event.

Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5. Merged with a later – now deleted – post. You can edit your posts for 24 hours. Please don’t shout[Helmut]
ping4santosh
☆

India,
2020-03-11 12:22

@ ping4santosh
Posting: # 21243
Views: 2,032

## Immediate release fixed dose combination product

Dear Ohlbe,

Best wishes,
SKM

Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! You even included the link to the post explaining why TOFU is strongly discouraged in the Forum. BTW, you replied to yourself and not to Ohlbe. Relax; see also this post #9.
This is the first warning. [Helmut]
Ohlbe
★★★

France,
2020-03-11 14:24

@ ping4santosh
Posting: # 21246
Views: 1,987

## Immediate release fixed dose combination product

Dear SKM,

We all post in our free time. See also also this post #9. To quote it: A reasonable waiting period is two weeks or if the thread has left the entry page of the forum. If you're in a hurry: hire a consultant.

» The dosing frequency for both the product is just one time treatment.

One-time antipyretic

» When we have both the product similar in it's posology, why do we need two pricks? Won't it suffice as the rationale of FDC?

Nope. Please read the guidance I pointed to you. Again, the "comfort" part is not sufficient if these are not two existing active principles which are always to be administered together, and this combination is written in both SmPC. So why this particular antipyretic, while there are so many on the market ? Why give an antipyretic SC or IM ? Many antipyretics are available as solutions or suspensions for patients who have difficulties swallowing tablets. If the subject is unable to swallow anything: he'll have an IV line and will be able to receive antipyretics available for IV administration, so no extra prick anyway.

» I don't see any reason for safety and efficacy study requirement.

Drug A may have an acceptable tolerability when administered alone. Drug B may have an acceptable tolerability when administered alone. It doesn't mean that if you inject drug A + drug B together at the same injection site, + some solubiliser not contained by drug A and drug B in their marketed formulations, you will still have an acceptable tolerability, particularly at the injection site.

Regards
Ohlbe
ElMaestro
★★★

Belgium?,
2020-03-09 13:50

@ ping4santosh
Posting: # 21228
Views: 2,126

## Immediate release fixed dose combination product

Hello ping4santosh,

in addition to what ohlbe has said, I'd like to mention that the guideline does open up for "substitution"; read section 4.2.
Substitution on its own may not be adequate justification for the existence of your FDC (that's the issue with the section Ohlbe quoted), and that's why many companies in your situation will need to prove that the monos are co-prescribed in your target markets (unless they wish to spend trillions on clin. trials to prove some superiority over standard care).
Co-prescribing info, in turn, is "easily" obtained from third party sources but you will also be paying an arm and a leg for that info. You will not find the reports by googling. It may nevertheless be exactly what you need to justify the FDC.

Check also if "initial therapy" applies with your product - section 4.3. I can't determine that from the info you wrote.

This week's list of things I absolutely detest: Corona virus, the which function in R, WIA-WIA interfaces for scanning under Windows 10, the Bee Gees, the smell of my fridge.

Best regards,
ElMaestro
Dr_Dan
★★

2020-03-11 11:47

@ ElMaestro
Posting: # 21240
Views: 2,045

## Immediate release fixed dose combination product

Hello ping4santosh,
Even if you aim at substitution indication (improvement of patient's compliance) presenting co-prescription data and therapeutic guidelines recommending the co-administration will not suffice as long as you are unable to present clinical data demonstrating safety and efficacy of the respective combination. IMHO it will be hard to identify a new FDC which can be approved without a phase III study (at least in western Europe).

Kind regards and have a nice day
Dr_Dan
ping4santosh
☆

India,
2020-03-11 12:21

@ Dr_Dan
Posting: # 21242
Views: 2,034

## Immediate release fixed dose combination product

Dear Dr Ken,

Thank you so much for your response. Why would we need effiacy and safety data when we don't plan to use any new solvent in the solution?

The FDC solution can be made at midway pH of 5 (one API is 8 and other is 4) with the help of existing solublizers that are safe and stable, we should only need to perform a Three way Three period Bioequivalence study with the API based 2 individual product with that of FDC to prove the bioequivalency of both the API for the FDC. I don't see any reason for safety and efficacy study requirement. Please correct me if wrong.

Cheers,
SKM

BTW, Dan  Ken. It’s unpolite to not even get the name of other members right. [Helmut]
Dr_Dan
★★

2020-03-11 13:44

@ ping4santosh
Posting: # 21244
Views: 2,006

## Immediate release fixed dose combination product

Dear SKM
Every new FDC needs clinical data for safety and efficacy unless it is a generic.

Kind regards and have a nice day
Dr_Dan
ping4santosh
☆

India,
2020-03-11 14:22

@ Dr_Dan
Posting: # 21245
Views: 1,983

## Immediate release fixed dose combination product

Dear Dr Dan,

Please accept my apology for spelling your name wrongly in my last draft.

Please allow me to ask you why you consider this as a new product? Both the APIs are registered as individual products in market and we are just combining both. Why would you call it as a new product that needs Efficacy and Safety data?

Thank you,
SKM
Ohlbe
★★★

France,
2020-03-11 14:40

@ ping4santosh
Posting: # 21249
Views: 1,983

## New product

Dear SKM,

» Both the APIs are registered as individual products in market and we are just combining both. Why would you call it as a new product [...]

Because that's what it is. You have to distinguish API and formulation. This will be a new combination of two existing API.

By the way, if I'm not mistaken it would also be considered a "new drug" in India, according to the New Drugs and Clinical Trials Rules, 2019, Chapter 1, § 2 (1) (w) (iii): a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form.

Regards
Ohlbe
ping4santosh
☆

India,
2020-03-11 16:34

@ Ohlbe
Posting: # 21256
Views: 1,965

## New product

» » Both the APIs are registered as individual products in market and we are just combining both. Why would you call it as a new product [...]
»
» Because that's what it is. You have to distinguish API and formulation. This will be a new combination of two existing API.

Dear Ohlbe,

Both the APIs are registered and marketed as separate formulation. We are mixing these two at same ratio into one formulation without adding any new excipients. I don't know why will it be considered as a new product. Can you guide me please?

Ohlbe
★★★

France,
2020-03-11 17:54

@ ping4santosh
Posting: # 21257
Views: 1,944

## New product

Dear SKM,

» Both the APIs are registered and marketed as separate formulation. We are mixing these two at same ratio into one formulation without adding any new excipients. I don't know why will it be considered as a new product. Can you guide me please?

Well, you are giving all the arguments yourself: up to now the two active substances are only marketed as separate formulations. You will be mixing them into one new formulation, which has never been tested or marketed before. Sorry, but I can't explain more.

Regards
Ohlbe
ping4santosh
☆

India,
2020-03-11 20:52

@ Ohlbe
Posting: # 21258
Views: 1,929

Cheers, SKM
ping4santosh
☆

India,
2020-03-11 12:18

@ ElMaestro
Posting: # 21241
Views: 2,031

## Immediate release fixed dose combination product

Hello!

Thank you so much for the thoughtful response. I appreciate your approach towards the feasibility of the FDC and its probability to get registered.

We have not done a great deal in terms of formulation development. We only evaluated the possibility/feasibility of having a solution formulation with the current set of solvents/ formulation pH, etc. for the individual products. It appears that we may be able to combine these products with all existing solvents which have a track record of safety.

If we assume that the FDC solution can be made at midway pH of 5 (one API is 8 and other is 4) with the help of existing solublizers that are safe and stable, what studies do we need to perform? My guess is that we need to perform a Three way Three period Bioequivalence study with the API based 2 individual product with that of FDC to prove the bioequivalency of both the API for the FDC. I don't see any reason for safety and efficacy study requirement. Please correct me if wrong.

Thanks a lot,
SKM

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