jag009
★★★

NJ,
2020-01-28 20:12

Posting: # 21092
Views: 2,516
 

 EMA: What do I need if I want to run an overdose study [Regulatives / Guidelines]

Hi all,

Need some help with running studies in Europe. If I want to run a PK study under each of the two scenarios:
  1. With a drug that is not approved in Europe but approved in USA, and i want to dose at a total daily dose higher than the total daily dose per label in USA.
  2. With a drug that is approved in Europe but at a higher total daily dose than that on the label.
What do I need to file? I know in US I need IND, in Canada I need a full CTA (30 days). what about in Europe? how long?

Thx
J
Helmut
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Vienna, Austria,
2020-01-29 16:52

@ jag009
Posting: # 21096
Views: 2,049
 

 EMA: What do I need if I want to run an overdose study

Hi John,

» Need some help with running studies in Europe. If I want to run a PK study under each of the two scenarios:

First of all: Are you talking about generic application (Directive 2001/83/EC, Article 10(1))? If yes, see below. Otherwise, please provide more details.

» 1. With a drug that is not approved in Europe …

Showstopper: “… reference must be made to the dossier of a reference medicinal product for which a marketing authorisation is or has been granted in the Union on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC, as amended.”

» 2. With a drug that is approved in Europe but at a higher total daily dose than that on the label.

Theoretically possible (Section 4.1.6 of the BE GL): “… if problems of sensitivity of the analytical method preclude sufficiently precise plasma concentration measurements after single dose administration of the highest strength, a higher dose may be selected (preferably using multiple tablets of the highest strength). The selected dose may be higher than the highest therapeutic dose provided that this single dose is well tolerated in healthy volunteers and that there are no absorption or solubility limitations at this dose.

» What do I need to file?

You need a very (very!) good justification.

Dif-tor heh smusma 🖖
Helmut Schütz
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Science Quotes
jag009
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NJ,
2020-01-30 04:32

@ Helmut
Posting: # 21100
Views: 2,019
 

 EMA: What do I need if I want to run an overdose study

Thanks Helmut!

» First of all: Are you talking about generic application (Directive 2001/83/EC, Article 10(1))? If yes, see below. Otherwise, please provide more details.

No it's not ANDA. Its an exploratory study (NDA?) with an ER formulation

»
» » 1. With a drug that is not approved in Europe …
»
» Showstopper: “… reference must be made to the dossier of a reference medicinal product for which a marketing authorisation is or has been granted in the Union on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC, as amended.”

(Sorry I updated my question, there is no question 1 and 2 anymore, just 1 question now)
An IR exists in Europe and an ER also exist in Europe but not the same as my so-called ER product. However, the other Euro ER product has safety issues and is currently off market. Euro IR is ok. I am thinking of dosing the ER of interest at a higher total daily dose than the max recommended dose of the Euro ER that is off the market.

» » What do I need to file?
»
» You need a very (very!) good justification.

Question, what's the standard turnaround time? UK? I mean after protocol approved by IRB and going thru the next approval stages(?)

Thx
John
Helmut
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Vienna, Austria,
2020-01-30 13:32

@ jag009
Posting: # 21103
Views: 2,016
 

 Can of worms

Hi John,

» No it's not ANDA. Its an exploratory study (NDA?) with an ER formulation

No (A)NDAs in Europe. :-D
The equivalent to NDAs are products approved by Directive 2001/83/EC (2001, latest amendment 2012), Articles 8(3) – which amongst others requires clinical studies.
For the equivalent of ANDAs see Article 10(2b).

» An IR exists in Europe and an ER also exist in Europe but not the same as my so-called ER product. However, the other Euro ER product has safety issues and is currently off market. Euro IR is ok. I am thinking of dosing the ER of interest at a higher total daily dose than the max recommended dose of the Euro ER that is off the market.

You cannot officially refer by any means to a product which is not on the market. However, the agencies have access to its data. Since the product was taken off the market for safety reasons and you want to go with yours at a higher daily dose it would raise eyebrows at least.

I think that a realistic option is a ‘hybrid application’ acc. to Article 10(3) comparing your ER with the IR product. Then you are free in selecting the dose and regimen of both. Still I have some doubts whether it would be acceptable to go beyond the maximum daily dose of the IR product. Details in the MR guideline Section 5. Additionally to the PK studies (can be a lot: SD/MD, food effect, if different strengths dose-proportionality) clinical studies are required.

Contrary to a generic application where the SmPC (European term for the label) is sufficient, you have to provide a complete IMPD to the IEC and the agency (see the applicable Legislation).

» Question, what's the standard turnaround time? UK?

Bye-bye to the UK on Feb 1st, 00:00… :cool:

» I mean after protocol approved by IRB and going thru the next approval stages(?)

Wait a minute! I’ve been there, done that. Without a scientific advice practically impossible. If you want to be on the safe side, opt for a centralized procedure at the EMA. If you succeed, the product is automatically authorized in all member states. The alternative is the decentralized procedure (DCP): You apply in one country first (the reference member state RMS) with the information that it is not a purely national application but that you will apply in others as well (the concerned member states CMS). Theoretically scientific advice(s) at the RMS sufficient. In tricky cases, I always go to more than one agency (not only the easy ones). Again in theory, once the RMS has accepted your application it has to defend its decision against the CMSs. Does not always work… My current preferred order: Sweden, Denmark, Germany, The Netherlands, Austria. Tricky one: Spain.

Dif-tor heh smusma 🖖
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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ElMaestro
★★★

Belgium?,
2020-01-30 15:12

@ Helmut
Posting: # 21105
Views: 1,976
 

 Can of worms

Hi jag,

I agree with Helmut.
My top three for scientific advice is Sweden, Sweden, and Sweden.
You will of course not fall for the temptation to take sc. advice in the countries which are the most attractive business-wise.

It will likely be a 10(3). This is Europe, so if the study is conducted here you will be facing an IEC, not IRB, technically. And note that the IEC may be a bottle-neck. They can say no, even if the authority will say yes.

Try and discuss the case with different CROs, I think you find that several of them (in EU their numbers are limited) have been in situation before and have been discussing the matter with other sponsors + authorities as well as with IECs.
What are you actually going to measure? :-)

I could be wrong, but...

Best regards,
ElMaestro

"Pass or fail" (D. Potvin et al., 2008)
jag009
★★★

NJ,
2020-02-03 20:28

@ ElMaestro
Posting: # 21134
Views: 1,490
 

 Can of worms

Hi ElMastro,

» Try and discuss the case with different CROs, I think you find that several of them (in EU their numbers are limited) have been in situation before and have been discussing the matter with other sponsors + authorities as well as with IECs.

Well my predecessor ran the IR SS study (over the total daily dose) many years ago and she ran it in UK. Not sure if she explored many European countries. She didn't do in US due to need for IND.

» What are you actually going to measure? :-)

You mean what fluid? Blood and Urine sampling. Will measure parent and metabolites, and something new (some sort of marker) if the analytical method of interest is available (to be confirmed) :-D

Thx
J
jag009
★★★

NJ,
2020-02-03 20:34

@ Helmut
Posting: # 21135
Views: 1,504
 

 Can of worms

Thanks Helmut!

Would it make my life easier if a similar study was approved and carried out for the IR counterpart (yes at doses above max total daily dose) many years ago? Both IR and ER (here and other countries that have the ER) have the same max total daily dose limit.

» I think that a realistic option is a ‘hybrid application’ acc. to Article 10(3) comparing your ER with the IR product. Then you are free in selecting the dose and regimen of both. Still I have some doubts whether it would be acceptable to go beyond the maximum daily dose of the IR product. Details in the..

Sorry I wasn't specific in previous response. This is a pure exploratory study, not intended for drug submission/registration.

» Wait a minute! I’ve been there, done that. Without a scientific advice practically impossible. If you want to be on the safe side, opt for a centralized procedure at the EMA. If you succeed, the product is automatically authorized in all member states. The alternative is the decentralized procedure (DCP): You apply in one country first (the reference member state RMS) with the information that it is not a purely national application but that you will apply in others as well (the concerned member states CMS). Theoretically scientific advice(s) at the RMS sufficient. In tricky cases, I always go to more than one agency (not only the easy ones). Again in theory, once the RMS has accepted your application it has to defend its decision against the CMSs. Does not always work… My current preferred order: Sweden, Denmark, Germany, The Netherlands, Austria. Tricky one: Spain.

So you mean (ok UK is out of the picture I guess in your example?), as an example, apply in Sweden (RMS) and apply to several other countries at the same time?

Thx
J
Ohlbe
★★★

France,
2020-01-30 17:32

@ jag009
Posting: # 21109
Views: 1,969
 

 EMA: What do I need if I want to run an overdose study

Hi John,

» Need some help with running studies in Europe.

When I read your post I interpreted it differently than Helmut and ElMaestro. So could you clarify your question: would you run those studies to register your drug in Europe, or to register it in the USA ? Helmut and ElMaestro answered with EU registration in mind, I understood you were asking about the authorisation of the studies.

» What do I need to file? I know in US I need IND, in Canada I need a full CTA (30 days). what about in Europe? how long?

CTA-like. You need an authorisation from the competent authority of the Member State where you would be running the trial + Ethics Committee opinion. You can submit to the authority and to the Ethics Committee in parallel. Timelines: supposed to be 60 days max + questions, according to Directive 2001/20/EC. Could be shorter depending on the Member State. Longer for products of biological origin. I can't say about the UK (especially after this week).

More details available in Eudralex volume 10. See for instance:
  • Guidance for the request to the Competent authority (CT-1)
  • Guidance for the application to the Ethics Committee
  • Guideline for the IMPD
These are national procedures - so you can expect some differences in the way it has been transcribed into national legislation, from one country to the next.

Being based in the USA, you would need a legal representative in the EU.

» An IR exists in Europe and an ER also exist in Europe but not the same as my so-called ER product. However, the other Euro ER product has safety issues and is currently off market. Euro IR is ok. I am thinking of dosing the ER of interest at a higher total daily dose than the max recommended dose of the Euro ER that is off the market.

You will need to justify in your protocol (subject safety) and plan the monitoring of the subjects accordingly.

Regards
Ohlbe
jag009
★★★

NJ,
2020-02-03 20:23

@ Ohlbe
Posting: # 21133
Views: 1,665
 

 EMA: What do I need if I want to run an overdose study

Thanks Ohlbe!

» When I read your post I interpreted it differently than Helmut and ElMaestro. So could you clarify your question: would you run those studies to register your drug in Europe, or to register it in the USA ? Helmut and ElMaestro answered with EU registration in mind, I understood you were asking about the authorisation of the studies.

Purely a exploratory study for the interest of science. No registration no drug submission. The drug is marketed in US (IR + ER), IR is available all over the world.

» Being based in the USA, you would need a legal representative in the EU.

Agree.

» You will need to justify in your protocol (subject safety) and plan the monitoring of the subjects accordingly.

Yes the protocol will implement a lot of medical monitoring, blood chemistry testing, etc. Subjects will be housed in clinic for the entire study.

Thx
J
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