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maulik963

2011-10-19 11:45

Posting: # 7519
 

Therapeutic Equivalence [Regulatives / Guidelines]

As per My knowledge,

Therapeutic Equivalence (TE) = Pharmaceutical Equivalence (PE) + Bioequivalence (BE)

but as per requirements for the dosage form to meet the bioequivalence criteria, they must be pharmaceutical equivalent/pharmaceutical alternatives.

so if bioequivalence term itself includes the condition of (PE) then is there any specific reason to mention (PE) in above equation?


Edit: Category changed. [Helmut]
Helmut
Homepage
Vienna, Austria,
2011-10-19 11:57

@ maulik963
Posting: # 7520
 

Therapeutic Equivalence

Dear Maulik,

IMHO your equation [TE = PE + BE] is valid for the FDA.
For EMA it’s [TE = (PE or PA) + BE].

In other words if the RLD is a tablet you can file an ANDA for a tablet only. In Europe you can apply for a generic market authorization for a capsule as well (according to definition in Directive 2001/83/EC Article10(2)(b)):

‘generic medicinal product’ shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.


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ElMaestro

Denmark,
2011-10-19 22:38

@ Helmut
Posting: # 7522
 

Therapeutic Equivalence

Dear HS,

» For EMA it’s [TE = (PE or PA) + BE].

Is it?
With the old NfG for BE being replaced by the 2010 guideline, I think the definitions are no longer well defined. If we need to figure out what PE and PA means, do we really need to look it up in the guideline that has now been replaced? I tried a quickie on Eudralex and didn't find it.
Anyways, in EU products falling under article 10.3 also involve TE so PD is an alternative to BE, and sometimes (nasal, inhaled, other locally acting) PD is the only way to demonstrate TE.
To me, in practice TE in EU seems be pretty much what WHO describes here.
(...and this document, by the way, has fingerprints of EU regulators all over it, doesn't it?)

"The difference is the same".

Messy.
Best regards,
EM.
Helmut
Homepage
Vienna, Austria,
2011-10-20 00:28

@ ElMaestro
Posting: # 7523
 

Therapeutic Equivalence

Dear ElMaestro!

» » For EMA it’s [TE = (PE or PA) + BE].
»
» Is it?
» With the old NfG for BE being replaced by the 2010 guideline, I think the definitions are no longer well defined. If we need to figure out what PE and PA means, do we really need to look it up in the guideline that has now been replaced? I tried a quickie on Eudralex and didn't find it.

Are you trying to confuse me? IMHO nothing has changed here. If you want to find the old NfG; it’s no more available anywhere in Valhalla – you may download a copy from BEBAC. ;-)
The current one more or less gives a quote of 2001/83/EC, Article 10(2)(b) in Section 1.2:

In applications for generic medicinal products according to Directive 2001/83/EC, Article 10(1), the concept of bioequivalence is fundamental. The purpose of establishing bioequivalence is to demonstrate equivalence in biopharmaceutics quality between the generic medicinal product and a reference medicinal product in order to allow bridging of preclinical tests and of clinical trials associated with the reference medicinal product. The current definition for generic medicinal products is found in Directive 2001/83/EC, Article 10(2)(b), which states that a generic medicinal product is a product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. Furthermore, the various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form.

(here we are again)



Equivalence Trials – Proving that apples are pears
by comparing the weight.
Stephen Senn (Guernsey McPearson's Drug Development Dictionary Part I, 2009)

You can’t really say “similar” if it’s the same again you want.
“Similar” means something different.
Anthony Burgess (Enderby Outside, 1968)

[image]All the best, Helmut Schütz.[image]
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maulik963

2011-10-20 10:45

@ Helmut
Posting: # 7525
 

Therapeutic Equivalence

Thanks for the details.

so the Equation TE=PE+BE is the process based where for the Drug product to be TE it must be first PE and then BE

its not like a mathematical equation where PE and BE are independent where both needs to be sum up to have answer TE.

Am i Correct?
yanliu622

Canada,
2011-10-20 19:16
(edited by Ohlbe on 2011-10-20 21:53)

@ maulik963
Posting: # 7527
 

Therapeutic Equivalence

Maulik,

TE, PE or BE are the type of equivalence studies. Which one is required would depends on the regulator and also the indication for the drug. FDA has a guidance for specific formulation in the following link.

TE is always conducted with patients. BE (in Vivio) is usually conducted with healthy subjects. PD (Pharmacodynamics) can be done on healty subjects of patients but usually done on patients. PE (in vitro) is always conducted in the lab. Most of the time the studies should be done in the following order to show Therapeutics Equivalence: PE ---> BE ---> PD or TE. For most of the generic drugs, PD or TE is not required. It does not mean TE=PE+BE. It just means PE and BE is sufficient to show equivalence of two drugs and TE is not required. A drug passes PE has a good chance to pass BE and a drug passes PE and BE has a good chance to pass PD or TE, but not always.

These are my understanding from my experience of working in the generic field for 9 years and dealing with EMEA and FDA regulations. Hope it helps.

Yan


Edit: FDA document linked. Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe]
ElMaestro

Denmark,
2011-10-20 20:14

@ yanliu622
Posting: # 7528
 

Therapeutic Equivalence

Hi yanliu,

» TE, PE or BE are the type of equivalence studies.

Wearing European goggles I see it differently.
I understand PE as just similarity in terms of brutto composition. BE on the other hand needs qualification by studies. These may be dissolution, PK or PD depending on the specific application and which side of the pond you are situated; BE has a slightly different meaning in US compared to EU.

While we are at it:
How do you experts out there distinguish essential similarity from TE in Europe? And what about ES vs TE vs BE in the US? Is TE truly when two products display same efficacy and safety but not necessarily same availability (rate and extent) at the site of action or whut?

Somebody hit me with a hammer, please.
JMCardot

France,
2011-10-24 12:18
(edited by Ohlbe on 2011-10-24 17:09)

@ ElMaestro
Posting: # 7535
 

Therapeutic Equivalence

Hello,

A simple question why you do not refer to the definitions which are in the old version of the EU guideline26 July 2001 CPMP/EWP/QWP/1401/98

JM


Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe]
ElMaestro

Denmark,
2011-10-24 13:51

@ JMCardot
Posting: # 7537
 

Therapeutic Equivalence

Hi JM,

» A simple question why you do not refer to the definitions which are in the old version of the EU guideline26 July 2001 CPMP/EWP/QWP/1401/98

I think it opens up a can of worms on steroids if we must rely on something in a document that has been formally replaced and made obsolete by another - perhaps not specifically in this context but very generally.

I could be wrong, but…


Best regards,
ElMaestro

Recipe for success: Treat guidelines like variable constants. And please throw all IVIVC papers for OIPs into the Thames.
JMCardot

France,
2011-10-24 21:16

@ ElMaestro
Posting: # 7539
 

Therapeutic Equivalence

Hello,

Have also a look on http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2011/06/WC500107873.pdf which gives another definition not better and in contradiction with the definition given for bioequivalence in http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/12/WC500099907.pdf

Both documents being not so old (< 1 year) but I agree not compulsory and do not help to define adequatly the terms! I could be mistaken but when a term is used it must be defined and unless a revised definition is given the old one is valid. I know it is another age way of thinking. I stop here.

JM


Edit: Dear Jean-Michel, you are really consequent! Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Helmut]
Helmut
Homepage
Vienna, Austria,
2011-10-24 22:15

@ ElMaestro
Posting: # 7540
 

Going Off-Topic

¡Señor!

» I think it opens up a can of worms on steroids …

Worms on steroids?

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