Regulatory Focus™ > News Articles > EMA, Drugmakers Weigh FDA Draft Guidance on Physiologically Based PK Analyses

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Posted 13 February 2017 | By Zachary Brennan 

EMA, Drugmakers Weigh FDA Draft Guidance on Physiologically Based PK Analyses


With an eye toward more harmonization, the European Medicines Agency (EMA) earlier this month weighed in on the US Food and Drug Administration’s (FDA) draft guidance on physiologically based pharmacokinetic (PK) analyses, alongside pharmaceutical companies including Novartis, Merck and Bayer.


EMA’s Pharmacokinetic Working Party (PKWP) and the Modelling and Simulation Working Group (MSWG) are developing a “Guideline on the Qualification and Reporting of Physiologically Based Pharmacokinetic Modelling and Simulation,” with a public consultation that ended 31 January 2017.

As such, the PKWP and MSWG comments are meant to further harmonize FDA and EMA guidance.

“We are assuming that the PBPK reports presented will be the same to the two agencies and therefore that it could be of value to have a more harmonised view of what to include in a PBPK report,” EMA says.

More specific comments deal with the “materials and methods” section of FDA’s draft guidance, and others on modeling parameters, simulation design and software.


Novartis praised the draft and said it will provide for opportunities to use mechanism-based physiological “systems biology” models to support drug development and licensing.

In terms of improvements, Novartis said the draft guidance may benefit “by leveraging and aligning to the Population PK guidance to ensure consistency in practice, documentation and reporting structure since these two approaches (bottom-up and top-down) are not different in its end goal to develop robust models to enable simulation (aka extrapolation) of unknown scenarios (FIH, bridging, chemical-structure optimization, DDI, special population).

“The confidence to do so requires validating the uncertainty in the precision of the parameter estimates requiring different methods of validation since the top-down approach focuses on the uncertainty of the data to estimate the parameters whereas the bottom-up approach requires sensitivity analysis of the referenced parameters to confirm plausibility,” Gretchen Trout, head of North America policy and FDA liaison, wrote.


Merck, meanwhile, is seeking to expand the scope of the guidance to include supplements of new drug applications and biologics license applications.

Additionally, Merck says non-clinical data should be included in this guidance, and that it should “allow for more flex

ibility when such data are not available. We also note that the guidance would be strengthened by including a section on ‘Equations Describing the PBPK Model,’ along with an explanation for why each element in the model was selected.”


And Bayer also thanked FDA for its efforts but noted that the structure and content of the guidance “is ideal if you are running one simulation, however, if you are running several simulations in the same development program, one will have duplicative information in each of the simulation reports. Therefore, the guidance should account for development programs that have multiple simulations and avoid redundancies in each report.”

Docket for Physiologically Based Pharmacokinetic Analyses--Format and Content; Draft Guidance for Industry


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