Melkor
☆    

Greece,
2015-03-02 13:22
(3314 d 17:41 ago)

Posting: # 14522
Views: 5,748
 

 Locally applied drugs [Regulatives / Guidelines]

Greetings,

I was wondering what are the exact requirements for a generic cream formulation concerning clinical data. According to EMA guidelines therapeutic equivalence is required to be demonstrated nevertheless; would a biowaiver for a locally non-systemic cream-lotion be acceptable in case relevant in vitro data is provided? :confused::confused::confused:

Thank you.
nobody
nothing

2015-03-02 13:27
(3314 d 17:36 ago)

@ Melkor
Posting: # 14523
Views: 5,052
 

 Locally applied drugs

Hi to Greece!

Besides the infamous vasoconstriction test (local glucocorticoids) I personally know no validated, regulatory accepted models for BE of locally applied locally acting dermal preparations.

The devil lies in the word "relevant" for your proposed in vitro models...

;-)

Kindest regards, nobody
Melkor
☆    

Greece,
2015-03-02 13:43
(3314 d 17:20 ago)

@ nobody
Posting: # 14524
Views: 5,022
 

 Locally applied drugs

I guess that a therapeutic equivalence study is then unavoidable.
:-(:-(


Apologies for sounding a bit ignorant but unfortunately i don't have previous experience in pharmaceutical creams or lotions.

:lookaround::lookaround:



Edit: Merged with a follow-up post. You can edit your original one within 24 hours after posting. See also the Forum’s Policy. [Helmut]
ElMaestro
★★★

Denmark,
2015-03-02 13:48
(3314 d 17:15 ago)

@ Melkor
Posting: # 14526
Views: 5,059
 

 Locally applied drugs

Hi Melkor,

❝ I guess that a therapeutic equivalence study is then unavoidable.


In some cases you can get acceptance to do a comparative PK-study even if the substance isn't really supposed to be in the blood. It is technically quite challenging.
You better fire up the API6000 or higher...:-D

Pass or fail!
ElMaestro
nobody
nothing

2015-03-02 15:32
(3314 d 15:31 ago)

@ ElMaestro
Posting: # 14527
Views: 5,025
 

 Locally applied drugs

Hi Denmark!

Are there any EPARs or stuff like that out there on positive examples?

Any details (publicly ;-) ) available on the class of compounds involved?

Definitely an approach to be confirmed by a well-prepared Sci Adv, I guess :-)

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2015-03-02 15:42
(3314 d 15:21 ago)

@ nobody
Posting: # 14528
Views: 5,012
 

 Locally applied drugs

Hi nobody,

❝ Are there any EPARs or stuff like that out there on positive examples?

❝ Any details (publicly ;-) ) available on the class of compounds involved?


None that I know of. These things tend to fail.

❝ Definitely an approach to be confirmed by a well-prepared Sci Adv, I guess :-)


Yes and also a technical evaluation. It is all about the LLOQ. An agonising choice: Do you wish to do the technical feasibility first (perhaps even not knowing the absorption / prospective plasma levels) or do you want the sc. advice first? It's going to cost $$$ before you get started.

Pass or fail!
ElMaestro
ioanam
★    

Romania,
2015-03-19 15:44
(3297 d 15:19 ago)

@ nobody
Posting: # 14578
Views: 4,444
 

 Locally applied drugs

Hello everybody

you can find the PAR for Diclofenac topical where the clinical study was performed according to the CPMP/EWP/239/95 final (the guidance currently in use for generic topical products).
Please follow the link: https://docetp.mpa.se/LMF/Diclofenac%20Orifarm%20gel%20ENG%20PAR.pdf

Kind regards,
Ioana
nobody
nothing

2015-03-19 16:20
(3297 d 14:43 ago)

@ ioanam
Posting: # 14579
Views: 4,421
 

 Locally applied drugs

Hi!

Nice! Would like to see the whole Assessment/Clin Study Report to learn how they confirmed sensitivity of the study design employed to detect relevant differences in the performance of the formulations studied... :-D

Kindest regards, nobody
Dr_Dan
★★  

Germany,
2015-03-02 16:56
(3314 d 14:07 ago)

@ Melkor
Posting: # 14529
Views: 4,967
 

 Locally applied drugs

Dear Melkor
In contrast to systemically available medications, there are very few possibilities for proving the bioequivalence of topically applied medications without a clinical study on patients (e.g. vasoconstriction test for corticosteroids). Nevertheless, for some substances, it is possible to demonstrate bioequivalence by dermatopharmacokinetic parameters using Raman spectroscopy. If you do not know if your drug provides a Raman signal or measurable concentrations it would be necessary to perform a pilot study:

Aim: Evaluation with pure API if the drug provides a Raman signal and if the expected local concentration in the epidermis are sufficient for measurement
If yes: Evaluation oft he local concentrations of your drug in the skin of human subjects using a positive control (reference)
Detection depth 50 µm (maybe deeper)
Result: Conclusion if a pivotal study would provide reasonable data with regard to bioavailability
Costs: ca. 10.000 €
If the pilot study shows that concentrations can be measured a pivotal study can be conducted.
Study with 20-30 subjects
Right- left-comparison of test and reference formulation
Costs: ca. 150.000 €
Result: Comparable kinetic of the local adapalene concentrations in the upper skin (to a depth of 50 µm) over time

Of course such an approach must be discussed with the regulatory authorities in a Scientific Advice before initiating the studies in order to gain acceptance.

I hope this helps.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
nobody
nothing

2015-03-02 17:01
(3314 d 14:03 ago)

@ Dr_Dan
Posting: # 14530
Views: 5,025
 

 Locally applied drugs

Hi Tschörmani!

Any scientific/regulatory publications on this approach?

You get a time-resolution, I guess, but there is no way to assess differences in the depth of penetration, or?

Kindest regards, nobody
Dr_Dan
★★  

Germany,
2015-03-02 17:22
(3314 d 13:41 ago)

@ nobody
Posting: # 14531
Views: 5,002
 

 Locally applied drugs

Dear nobody

Caspers PJ, Lucassen GW, Carter EA, Bruining HA, Puppels GJ. In Vivo Confocal Raman Microspectroscopy of the Skin: Noninvasive Determination of Molecular Concentration Profiles. J Invest Dermatol. 2001;116(3):434–42. doi:10.1046/j.1523-1747.2001.01258.x. open access.

AFAIK you are right, there is no way to assess differences in the depth of penetration since this method is limited to 50 µm (maybe deeper). But this should work for locally applied and locally acting products. Otherwise in case of deep penetration the drug substance would become systemically available, right?

Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
nobody
nothing

2015-03-02 17:31
(3314 d 13:33 ago)

@ Dr_Dan
Posting: # 14532
Views: 5,007
 

 Locally applied drugs

❝ ....Otherwise in case of deep penetration the drug substance would become systemically available, right?


Maybe, but what you are looking for are differences between formulations, e.g. if your new formulation results in higher systemic availability than the originator, which might result in safety issues. Would be hard to determine from the skin data (IIRC there are some Scotch-tape "stripping" models, too, on dermal penetration, resulting in a little more resolution of penetration depth).

A combination with systemic data (ala Maestro) appears mandatory to me, at least in most cases. But maybe I'm even more conservative than Europ. regulators? :-D

Kindest regards, nobody
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