Hi Gregory,
I would not consider that either position you propose would be viewed by FDA as "pushy." If the proposed limit for an impurity is covered by toxicology studies, that provides support to "exceed" the ICH limit, recalling that ICH limits are for intended for commercial products (though FDA and industry typically use ICH limits even during clinical development in the absence of "development limits"). During the clinical development stage, I approach meetings with regulatory agencies to help define what's possible to create flexibility for my organization. Whether it's impurities limits, toxicology safety factors, or clinical trial design, I try to determine what the regulators might accept, in essence, defining a "design space" of sorts. If FDA agrees to your proposal for wider impurities limits, for example, you may still choose to be well inside those wider limits, but at least you have created room for your company in case a new batch has higher levels of the impurity, or degradation occurs on stability. I routinely ask these kinds of questions because I want o know what the regulators will accept--I gave up a long time ago betting on what regulators would allow or not allow as I was surprised (usually favorably) too many times.
Asking clearly unreasonable questions costs you and your organization credibility. You should ground the "what's possible," though, in reality to a reasonable extent. For example, proposing an impurity limit of 5% when the toxicology batch had 1% and the clinical batch is 0.5% is probably a bridge too far; however, FDA would still give you an answer of what they'd accept though it may be tighter than you otherwise want. You want to build up FDA's confidence in you as a regulatory professional and in your organization as trustworthy partners in the drug development process, which may give you some leeway, especially early in development.
There are some really good Regulatory CMC consultants you might contact to give you critical feedback on your proposal before sending it to FDA. Direct message me and I can give you some names, if you'd like.
Good luck!
------------------------------
Mark A. De Rosch, PhD, FRAPS
Laconia NH
United States
------------------------------
Original Message:
Sent: 05-Jul-2023 10:12
From: Gregory Wei, Ph.D. RAC
Subject: What is the downside of asking FDA pushy questions?
Hi, I am preparing a CMC meeting package for a clinical phase drug. I got pushed by management to ask pushing questions. The idea is that we have nothing to lose if FDA does not agree with us. One of the examples is to ask for one higher-than-the-ICH limit for one impurity based on real thin data. In case got lucky, no need to spend on additional experiments. Another example is to ask if it is acceptable to make one bridging batch to double the tablet counts per bottle while retaining the validity of the primary batches including the process and expiry. If FDA does not agree, we just fall back to the original package.
In the past, my mentor carried such an air around her that people did not dare to ask that kind of question. Now that I am on my own and look weak...the floodgate opens. My question is what is the downside of asking FDA pushy questions? What do we have to lose if FDA does not agree with us?
Thanks!