[e-drug] therapeutic equivalence of different dosage forms?

E-DRUG: therapeutic equivalence of different dosage forms?
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dear E-druggers,

I would like to ask your help and advice regarding a question I have
been requested to answer. Company A, is producing the generic medicine
X, an antifungal, IV infusion, packed as 100 ml. Company B, after
marketing the original, brand product (to which X is equivalent) packed
as 100 ml, now is marketing also a 200 ml package, the same
concentration (y mg/ml). Now company A, is asking us whether there are
therapeutical differences between these two packages. In other words,
there is any therapeutic difference between 2x 100 ml of generic and 200
ml of brand product, both having the same concentration, and the product
being an IV infusion? In a tender for 200 ml, could company A
participate with its 100 ml form?

For me the answer seems self-obvious, but I could be wrong, that is why
I am asking your help.

Thank you,
Best regards,

Robert Ancuceanu,

Pharmaceutical General Directorate
Ministry of Health
Bucharest, Romania,
1-3 Cristian Popisteanu Street
tel: 040 21 3072550
e-mail: ancuceanu77@ifrance.com
        anro@ms.ro

[moderator's comment: IV fluids should be 100% available? Anyway, let us hear from the drug regulators what they think about 2x100 vs 1x200mL. WB]

E-DRUG: therapeutic equivalence of different dosage forms? (4)
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Dear Robert,

Since this is a real situation I see in my day-to-day work, and, believe it or not, I have a 100ml, 2mg/ml infusion of an antifungal on my desk awaiting evaluation! I will share my views with you.

First of all, therapeutic activity does not reside in the packaging, even though it can be negatively affected by it.

Secondly, in a tender, a medicinal item is defined by all technical parameters, including packaging, and any changes will affect the conclusions that might be drawn during evaluation of a bid, including price.

Therefore, if the invitation- to-bid specifically required bids for 100ml and not 200ml, the latter is definitely not responsive to the tender should be treated as such.

When we procure medicines for programmes, we should always remember that health staff training guidelines and manuals often refer to package size and any changes in this can lead to unnecessary confusion.

Having said this, however, there are often cases where, all being equal, "total value" can vary with differences in package, provided that the latter does not negatively influence therapeutic activity.

Finally, a company that decides to change a packaging should be asked a few more questions regarding stability of the medicine in the new package.

Regards

Murtada M. Sesay
Technical Officer (Pharmaceuticals)
UNICEF Supply Division
UNICEF Plads, Freeport
DK-2100
Denmark
Telephone: +45 3527 3098
Facsimile: +45 3526 9421
E-mail: msesay@unicef.org.

E-DRUG: therapeutic equivalence of different dosage forms? (5)
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Dear Robert,

In general for parenteral formulations bioequivalence studies do not have to
be performed to substantiate therapeutic equivalence, provided that "the
product is to be administered as an aquaous intravenous solution containing
the same active substance in the same concentration as the currently
authorised product". Because as a rule bioavailability of an intravenously
administered drug is 100%. This also applies to "a formulation intended for
orther parenteral routes, e.g. intramuscular or sc, if the product is of the
same type of solution (oily, aquaous) contains the same concentration of the
same active substance and the same or comparable excipients as the currently
approved medicinal product." Many of the aquaous IV solutions contain very
simple excipients that do not interfere with absorption of the product or
cause specific untoward reactions in specific patient groups as suggested by
Maciulaitis. (A common example of such a problem might be allergic responses
in sensitive populations in case of oral drug formulations where the
excipient e.g. carboxymethyl cellulose is replaced by lactose.) Of course
assuming that the excipients used are safe and have itself no impact on the
efficacy of the product.

This (somewhat) formal answer comes from the Note for Guidance on the
investigation of bioavailability and bioequivalence (CHMP/EWP/QWP/1401/98)
by the European Medicines Agency (EMEA). This is the European Regulatory
Body's guidance for the industry when applying for therapeutic equivalence
of a generic product. You can freely download that from the EMEA website.

So from a (European) regulatory point of view, the products can be
considered therapeutically equivalent when 2 X 100 ml is administered
instead of 1 X 200 ml. But it may be important to take into consideration
the remarks made by Murtade Sesay on the pack-size and guidelines. Of course
reliability of the supplier and quality control of the chain of procurement
are probably other issues you may want to consider (but this is not my field
of expertise.)

With regards,

Peter G.M. Mol
Pharmacist-researcher
Department of Clinical Pharmacology
University Groningen
P.O. Box 196
9700 AD Groningen
tel. +31 50 3638313
fax, +31 50 3632812

E-DRUG: therapeutic equivalence of different dosage forms? (6)
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Respected Mr. Robert Ancuceanu,

In my opinion, there will not be any difference in the therapeutic efficacy
of 100ml vs 200ml as long as the composition remains same and there is no
change in packaging material specifications apart from the volume.

In any case, in my opinion, manufacturer should conduct stability study on
200ml pack against the specification set for 100ml product and if stability
result is satisfactory, the approval should be granted.

Regards,

Rakesh Chaurasia
Dy. General Manager-Drug Regulatory Affairs,
Macleods Pharmaceuticals-Mumbai
India
chaurasiarakesh@macleodspharma.com