Bioequivalence and Bioavailability Forum • Atorvastatin study design

bioequa
☆

Bosnia and Herzegovina,
2011-01-04 12:25
(5650 d 12:46 ago)

Posting: # 6393
Views: 8,837

Atorvastatin study design [Design Issues]

Hello,
I have some doubts about designing bioequivalence study for atorvastatin ftbl.

First of all, as You all know, according to new EMEA BE guideline, it is not necessary to determine or evaluate metabolites anymore. But we are still afraid that some agencies might ask for metabolites, at least for explanatory purposes. Do we need to measure metabolites in BE study?

And second, if we provide evidence of high variability (during pilot study), is it too complicated to define in Pivotal study Protocol acceptance criteria for Cmax to be widened. What are Your experiences with Drug Agencies about this Cmax widening?

Helmut
★★★

Vienna, Austria,
2011-01-04 16:23
(5650 d 08:48 ago)

@ bioequa
Posting: # 6394
Views: 7,794

Atorvastatin study design

Post reply

Dear bioequa!

❝ […] according to new EMEA BE guideline, it is not necessary to determine or evaluate metabolites anymore.

Generally yes. Exceptions are inactive pro-drugs, where measurement is not possible. For atorvastatin the former most likely holds, but not the latter.

❝ But we are still afraid that some agencies might ask for metabolites, at least for explanatory purposes. Do we need to measure metabolites in BE study?

Depends on the country. For the [image]

FDA (10/2010) you should submit ortho and para-hydroxy atorvastatin (profiles, AUC, and C_max: supportive only – no comparison).

❝ And second, if we provide evidence of high variability (during pilot study), is it too complicated to define in Pivotal study Protocol acceptance criteria for Cmax to be widened. What are Your experiences with Drug Agencies about this Cmax widening?

No way. Even according to EMEA’s old Q&A-document (2006) you had to show high variability of C_max in the same study. Any reference to a pilot study or literature data was (and is) not acceptable. Widening of the acceptance range for C_max to 75–133% (2001 EMEA-guideline and countries still following this rule – like Australia, ASEAN states, …) required a

demonstration of high variability of the reference (CV_WR >30%) in a replicate design, and
justification of lacking safety/efficacy issues.

According to the current European guideline you may scale the acceptance range for C_max (30%<CV_WR≤50%), but still have to address safety/efficacy.

For the FDA you may scale both the acceptance ranges for AUC and C_max (no upper limit of CV_WR – but actually limited by the restriction of the GMR of within 80–125%).

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

bioequa ☆ Bosnia and Herzegovina, 2011-01-04 16:44 (5650 d 08:27 ago) @ Helmut Posting: # 6395 Views: 7,641	Atorvastatin study design Post reply
	Thank You for Your prompt answer. What would You suggest? 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! [Jaime]

Helmut
★★★

Vienna, Austria,
2011-01-04 18:54
(5650 d 06:17 ago)

@ bioequa
Posting: # 6396
Views: 7,841

Atorvastatin study design

Post reply

Dear bioequa!

❝ Thank You for Your prompt answer. What would You suggest?

Without further information – nothing.
When it comes to highly variable drugs, countries’ regulations are very different (see this post). The only European public assessment report I could find was on Tevas’ issued by the Hungarian authority (RMS) back in 2009 (CMSs: AT, BE, BG, CZ, DE, DK, EE, EL, ES, FR, IE, IT, LT, LU, LV, NL, NO, PL, PT, RO, SI, SK, UK). According to this report in a scientific advice (October 2008) it was suggested to give an acceptance range for AUC and C_max of 2-OH atorvastatin. It’s unclear to me whether bioequivalence was shown for parent, metabolite, or both (BTW, 4-OH was also measured).

EMA has no intentions to come up with a list of highly variable drugs and/or product-specific guidelines (which would end the parent/metabolite discussions). The only tool we have are the public assessment reports – which lag behind. The guideline is in force for only five months right no now. I don’t expect that there’s a single PAR according to the new GL already available at the European Product Index.

In your original post you asked about the acceptability of parent/metabolite and widening of the acceptance range in different countries. As already said – points of view are different. If you plan a study for one region (EU, US, :blahblah:

), your chances to get an approval in another region can be rated from likely to nil. Examples:

Australia follows EU’s 2001 GL, but you have to use the Australian reference product. EMA’s 2010 GL is currently in the evaluation phase. Outcome unclear.
RSA has their own guidelines and require the South African reference product – unless you can show that the reference in the study is similar in vitro to RSA’s reference.
Whilst it is possible to run a conventional BE study for US and EU (6-sequence, 3-period) with both a European reference and US’ RLD - if you think about scaling: no way.
And so on and so forth…

Any submission of a dossier which was planned to follow closely one region’s guidelines to another region is more or less risky. The worst I have seen was the application of a HVDP to Saudi Arabia 19 years after the study was performed in Germany. At that time it was state of the art to run a study only in steady state in order to reduce variability. And the validation of the analytical method was, well… Took ages, deficiency letters and answers went to and fro and finally the dossier was retracted.
See also ElMaestro’s observations.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes