Bioequivalence and Bioavailability Forum

Hi Petra,

as a Dutch you are happily skating on thin ice.

❝ In the past, the innovator also had a second (twice as high) strength on the market. We would like to register both strengths in the EU as a generic submission.

Important question: Do you have any clues why the innovator took the highest strength off the market? If anything (!) might be related to safety, I would be very wary. I’m pretty sure this is not a pure generic application any more. I guess you have to walk the hybrid track.

❝ Therefore, I have planned a BE study with the highest generic strength versus 2* the innovator strength. This means that the same (test and reference) single dose is given.

In principle OK – if you can rule all questions out.

❝ Should the single dose follow the dosage regimen of the innovator? As stated in the SmPC of the innovator, the dosage regimen is x mg, divided in two doses.

That’s the crucial point. The higher strength is off the market and according to the SmPC it seems to be clear taking the maximum daily dose at once is not a good idea – or worse – there might even be inno­va­tor’s data filed at authorities which led to this restrictive posology.

❝ In our BE study we wil give (for our test product) the total daily dose in one single dose, instead of giving it in two divided doses. Is this allowed?

❝ I have checked the EU BE Guidance, but could not find information on this issue. The only point which is stated in the Guidance is for steady state studies: "...the administration scheme should follow the usual dosage recommendations".

Check out what the draft tells about supra-therapeutic doses. Was mentioned if the analytical method is not sensitive enough. EMA received comments that such an approach is not ethical. Some left-overs in section 4.1.1

[…] given that a multiple dose study is less sensitive in detecting differences in C_max, this will only be acceptable if the applicant can adequately justify that the sensitivity of the analytical method cannot be improved and that it is not possible to reliably measure the parent compound after single dose administration taking into account also the option of using a supra-therapeutic dose in the bioequivalence study (see also section 4.1.6).

and section 4.1.6

[…] 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.

The justification is an insensitive method. Even in that case, who would take the risk/responsibility of administering a supra-therapeutic dose? Try to find out why the highest dose was taken off the market, and – if in doubt – go for a scientific regulatory advice. IMHO, you play with fire.

Other opinions mostly welcome!