Bioequivalence and Bioavailability Forum

Dear TEDIC!

You are raising very interesting – and mainly also difficult to answer – questions…
I will try to start the discussion by giving a couple of desultory thoughts.
These thoughts will be contradictory anyway, but may give you some new perspectives.
Just to keep terminology high: in your case we should talk about 'relative bioavailability' (not BE); although we have the special situation, where test and reference are interchanged.

To go with the NfG on BA/BE first (Section 5.1.2 Oral solutions):

In those cases where an oral solution has to be tested against an oral immediate release formulation a comparative bioavailability study will be required unless an exemption can be justified (see 5.1.1).

Section 5.1.1 is essentially a reference of the BCS. Please also consult with the recent Concept Paper.
Remark: Classification in the EU is less strict that in the US (literature data often accepted instead of CaCo2-experiments).

❝ 1. Is it necessary to show bioequivalence in this situation? Could we not argue that for a drug where dose is titrated to a 'biomarker' what is important is to show that is a robust formulation, that performs to an acceptable level of variability?

Yes you can argue that way (especially for a solution). But keep in mind that many other drugs are dose titrated according to safety/efficacy (antiepileptics, antidepressants,...), and still BE is required. We had this debate in the early 90ies (average BE, prescribability - population BE, switchability - individual BE). In current clinical practice quite often patients are switched from formulation A to formulation B during therapy, although in the strict sense such a practice is not supported by the common ABE approach. Some regulators therefore advocate more stringent limits for some classes of drugs (e.g., Denmark).

❝ 2. Or is it better to do develop a paediatric investigation plan that involves a 'comparison' with a marketed tablet, but which is not necessarily looking for 'bioequivalence'. So for example if the liquid formulation is shown to achieve a mean relative exposure to the tablet of 0.7, then this is what will go on the label. Remember, this should not matter a lot since doses are titrated to neutrophil count.

I don't know whether this approach is 'better'; I would consider it 'safer' in terms of a successful application…

❝ 3. If you think bioequivalence will need to be shown, do you have any suggestions for the best way to conduct such a study, bearing in mind the variable nature of the drug, the patients population (oncology, children).

Oh dear, this will be very difficult. You will have to work in steady state only - which many regulators do not like, because of lacking sensitivity detecting differences in C_max. If you are testing a solution vs. a tablet, I would guess the major concern would be equivalence in C_max (safety!). I don't know whether this is possible at all; it depends on the drug…
Which BCS class is your drug belonging to?
Class I would be great, Class III not so good, but still fine.
What's the dissolution characteristic of the tablet? You may apply for a biowaiver (normally it goes the other way 'round, namely IR vs. IR, but I think in your case the major concern would be a substantial faster C_max).

If you opt for a biostudy…
Repetitive blood sampling in children also raises a lot of ethical concerns. One option would be to show BE in adults, and then continue with a population PK study (sparse sampling) in kids (see Section 4.2.6 of the Paedriatic PK Guideline. You will have to validate such a study beforehand (which is also not trivial). You also may try to get a waiver for the paediatric study at all due to ethical reasons (I haven't seen a single BE-study performed in children for methylphenidate; all studies were performed in adults).
Another point: though I have heard of BE studies of methotrexate in patients, I have performed single dose studies in healthy (adult) subjects, which were accepted by the MHRA.

As promised, some thoughts, no definite solution, but hopefully new ideas from the far side.