Content and Format Questions – One of the Most Powerful Tools in the Submission Tool Box

An FDA Refusal to File (RTF) letter is a formal notification sent to a pharmaceutical company when a New Drug Application (NDA) or Biologics License Application (BLA) is so incomplete or poorly organized that the FDA cannot begin a substantive review. Issued within 60 days of submission, this letter acts as a "quality gate" to prevent wasted review resources on deficient submissions.

What can you do to eliminate the risk of receiving an RTF?

The answer is two-fold:

1.        One, a reviewer’s guide. When we are talking about big submissions, there is nothing more helpful than a reviewer’s guide– but in another blog post, we will dig into this and how AI can help you prepare one. Stay tuned.

2.        And two, a Format and Content Request for Written Response. Let’s dig into this one now...

Content and Format Agreement – Yes, Get the Agreement in Writing!!

One of the misses when interacting with the FDA is obtaining agreement regarding the Format and Content of an NDA or BLA Application. Sponsors limit conversations to more strategic efforts because they often assume that what worked for one division regarding a previous application will work this time around. But in doing so, they may be overlooking an opportunity to avoid an RTF.

With the FDA, I have learned that there are no stupid questions. Only questions that have been addressed in the various guidance or have not been addressed at all but may require specific discussion. And either way, it is more than okay to obtain at least a written agreement, regarding Content and Format, to ensure we are all on the same page. This approach leaves nothing to chance and eliminates surprises. There is nothing like trying to convince your co-workers that a particular strategy is too risky to try. Going straight to the horse’s mouth is often my best strategy.

Especially now, since we recently heard it from Makary himself that what was deemed necessary to be included in applications previously may not be the case now. And with the recent changing of the guard, who knows!? So, if you ask us, this uncertain moment is a crack in the door we should all walk through. Or at least ask the simple question – do I really need that?

4 Key Content and Format Questions You Should Ask Pre-submission (These are all questions we’ve asked to our benefit.)

• Narratives – Are there any narratives aside from those listed in the guidance that we should consider submitting?

• Case Report Forms – We are planning to provide the following CRFs according to the 2013 Guidance Electronic Source Data in Clinical Investigations Guidance for Industry, including a reviewer’s guide. Is there anything we should consider when submitting or preparing the guide?  Or we are not planning to provide XX CRFs for this reason. Does the Agency agree?

• Datasets – Our datasets will follow the November 2023 Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments Using Item Response Theory guidance. With that said, we are only planning to provide the following subset for this reason. Does the Agency Agree?

• Literature Reference – We understand that the FDA has extensive access to literature references. Is it necessary to include all references in the submission? We were only planning to provide and fully link the following types of references for this reason. Does the Agency Agree?

Now, truth be told, the FDA is very good at sending you back to the guidance where they have provided in detail their current thinking. But nothing is keeping you from asking well-thought-out questions to gain clarity when it’ is warranted. And we at SWOT believe that you never know what wins are waiting for you behind a perfectly worded question. Above all else, when in doubt, let us know if we can help you draft a clear and concise Content and Format query.