Bioequivalence and Bioavailability Forum

Hi Helmut,

I know this is a bit late comment.

But I draw your attention that draft guidance is focusing on plasma matrix. It should be more general to any validated body matrix (e.g. urine, saliva...etc, and I have sent this to FDA.

Nasir

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

Hi ElMaestro,

I linked your post to another active thread.

❝ There is an extremely important distinction here (site of action vs absorption) which is relevant to the way we potentially treat locally acting drugs, such as orally inhaled products or nasal sprays.

Yes, that’s a rather old contradiction. Talked about it with Vinod Shah and Les Benet in September. What’s written in the CFR is sumfink which went through the mills of US-legislation in the 1980s (or 1970s?). To get rid of the “site of action” would mean to change the law; the FDA decided not to walk that road. Current practice (i.e., what the guidances essentially mean) is “gets absorbed and becomes available in the systemic circulation”.

❝ So what's your take on this?

IMHO, the main assumption in BE is that similar concentrations at the site of action [sic] would lead to similar clinical effects. Now for the pitfalls:

• Due to the law of mass action in steady state [sic] we expect equal concentrations across com­part­ments and receptors. Hence, only in steady state it would be irrelevant from which site we sample.
  
• Once absorbed, transport from the central compartment to – optionally peripheral ones and – the receptors follows passive diffusion. If we have similar concentrations – even after a single dose – nothing to worry about. Receptor saturation follows wacky sigmoidal functions. Therefore, the rate of absorption is important.
  
• So after EV administration concentration in, say plasma, is a surrogate (of receptor-load), which is a surrogate (of clinical effect).
  
• In other words, whatever we measure, theoretically the “closer” we are to the receptors, the better.

Given that, plasma is the most convenient surrogate for many EV routes of administration. For pulmonary delivery it might be a PD measurement (note that the guidance is about PK endpoints!). In my under­standing that’s one major point of disagreement between FDA and EMA when it comes to plasma con­centrations after charcoal blockade. Seems that the FDA still see the site of action primarily and PK in plasma as too far “downstream”.

If still in doubt about FDA’s interpretation, ask Vinod or Les. Mehl-addresses upon request.

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Edit: Reading the guidance again, I think that it is mainly for formulations intended for systemic action (locally acting orally administrated ones are an exception). OIPs and other topicals (creams, gels, ointments) are not covered.

• 23–26: The guidance is generally applicable to dosage forms intended for oral administration and to non-orally administered drug products in which reliance on systemic exposure measures is suitable for documenting BE (e.g., transdermal delivery systems and certain rectal and nasal drug products).
  
• 58–60: For most products, the focus of BE studies is on the release of the drug substance from the drug product into the systemic circulation. During such BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the RLD.
  
• 66–69: As noted in 21 CFR 320.24, in vivo and/or in vitro methods can be used to establish BE. In general descending order of preference, these include pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.
  That’s the one place where PD studies are mentioned.
  
• 277–281: A suitably validated pharmacodynamic method can be used to demonstrate BE. However, we do not recommend pharmacodynamic studies for drug products that are intended to be absorbed into the systemic circulation and for which a pharmacokinetic approach can be used to establish BE.
  That’s the other.
  
• 75–78: […] the statutory definition of BE, expressed in terms of rate and extent of absorption of the active ingredient or moiety, emphasizes the use of pharmacokinetic endpoints in an accessible biological matrix, such as blood, plasma, and/or serum, to indicate release of the drug substance from the drug product into the systemic circulation.

Dear Dr. Gunasakaran!

❝ For applicants wishing to use variations of these study designs or analysis methods (e.g., a sequential design or scaled-average BE, we recommend that you submit a complete protocol for review and comment before starting the study."

Thanks for pointing that out (lines 125-127); it slipped through my attention. Apart from a potential delay – any recent experiences from our members how long the review process at the FDA takes? – I’m really fine with that.

• Sequential designs
  I’m positive about the acceptance of Potvin’s Method C and its derivatives. FDA’s CDER cosponsored PQRI’s studies and FDA’s Donald Schuirmann is one of the authors; these are the variants they recommended (not Method B!). See also product-specific guidances on Loteprednol Etabonate / Tobramycin (06/2012) and Loteprednol Etabonate (04/2013).
  
• RSABE
  Gives an opportunity to clarify whether
  • TYPE=FA0(1) instead of TYPE=FA0(2) might be used in evaluating the partial replicate design (due to convergence issues with the latter if unscaled ABE has to be applied) or
    
  • a fully replicated three-period design (i.e., TRT|RTR) is an acceptable alternative.

Hi,

❝ Oops New FDA states that "For applicants wishing to use variations of these study designs or analysis methods (e.g., a sequential design or scaled-average BE, we recommend that you submit a complete protocol for review and comment before starting the study", it means any Scaled Average BE protocol need to be submitted to FDA before study initiation .

Hmm.. But shouldn't one inform the agency if they elect to use a different design other than the partial/full RSABE, ABE (and others that FDA has published) anyway? Why is this a disappointment? They just don't want to think outside the box thats all (too many rules and politics to follow?).

At least they stated up front, otherwise they can reject your study at filing if they want to.

John

Hi Helmut,

❝ The consultation period will end next Wednesday. As of today only three brief comments have been submitted (two from India and one from South Korea.

why you don't send your above comments? Are the comments allowed and accepted only from companies? I find your comments are reasonable and rational.