After working for years to bring a drug to market, not to mention grinding the last several months preparing your NDA or BLA application, one of the most frustrating and disheartening roadblocks is receiving a Refuse to File from FDA. Receiving a Refuse to File means FDA won't even consider reviewing your application as it stands, and sets you back months if not more on your journey to drug approval. Read on to learn how to avoid a Refuse to File situation.
Engage with FDA Early
You may know that having a successful preNDA/BLA meeting with FDA can go a long way to ensuring a successful NDA/BLA submission. A preNDA/BLA meeting can help you and FDA align on key issues and expectations as well as determine whether additional data or studies are needed. In short, a preNDA/BLA meeting gives you a roadmap to follow to meet FDA's expectations. But in truth, your engagement efforts should start during your IND with your End of Phase 2 meeting and going all the way back to your preIND meeting -- or even an INTERACT meeting if you're developing a novel product with unique challenges. But there is still more you can do.
Get the Basics Right to Avoid a Refuse to File
First things first, you need to make sure you've got your basics down (where applicable), and a lot of these have to do with your application's completeness.
Submit your application in eCTD format, which has been mandatory since 2017.
Make sure to include completed, electronically signed, fillable application forms like Form FDA 356h).
Submit an environmental assessment, or provide sufficient information for an exclusion.
Make sure to submit English translations where applicable. There should be nothing in your application that isn't reviewable in English.
Include a statement for each nonclinical laboratory study that the study was conducted in compliance with 21 CFR part 58 (or include the reason for the noncompliance).
Include a statement with each clinical study that the study was conducted with IRB standards in 21 CFR part 56 (or was not subject to those regulations), and that it was conducted in compliance with the informed consent regulations in 21 CFR part 314.50 (or if not in compliance, include a reason for the noncompliance).
Ensure Your Application is Complete
The content and format of your application is what will make or break your chance at obtaining a successful drug approval. You can refer to 21 CFR part 314.50 for all the details of what you need to include, but here's a quick summary:
A completed application form
An index (which is the XML backbone, in the case of eCTD submissions).
Summaries (Module 2)
Chemistry, manufacturing and controls information about the drug substance and drug product (Module 3)
Nonclinical pharmacology and toxicology information (Module 4)
Human pharmacokinetics and bioavailability information (Module 5)
Microbiology information if the drug is anti-infective (Module 5)
Clinical Data (Module 5)
Statistical Information (Module 5)
Pediatric Use information (Module 1, 2 and 5)
Samples (upon request) and Labeling (Module 1)
Case report forms and tabulations (Module 5)
Patent information and certification (Module 1)
Claimed exclusivity if applicable (Module 1)
Financial certification or disclosure statement (Module 1)
Ask for Content and Format Advice or ESG Guidance (Before Submission) - Yes, you can do that!
Speaking from experience, for less traditional applications, don't be afraid to ask the FDA. Preparing a clear Content and Format proposal with diagrams and visuals (if needed) for the Agency and request their written feedback regarding their expectations for those things that are not already made clear in accessible published resources. This is a great way to eliminate RTF surprises. And remember, technical questions can be sent to the FDA's eSubs offices:
CDER at esub@fda.hhs.gov
CDER Datasets: edata@fda.hhs.gov
CBER at esubprep@cber.fda.gov
Electronic Submissions Gateway: ESGHelpDesk@fda.hhs.gov
Be Ready to Be Responsive After Submitting
Though it's not required, sponsors are typically given an opportunity to correct small deficiencies within the 60 day window where FDA is considering an NDA for filing. Here are some examples of what FDA might consider an "easily correctable deficiency."
Electronic navigational problems (bookmarks, hyperlinks, XML issues, etc.)
Electronic compatibility/readability with the FDA's system
Missing right of reference to information required
Incomplete or missing form 356h
Missing financial disclosure on Form 3454
Incorrectly worded debarment certification statement
Small amounts of missing data that have been collected but not submitted
Failure to submit the content of labeling in electronic structured product labeling (SPL) format
Keep in mind that a combination of the above deficiencies could result in a Refuse to File if FDA believes there are too many issues to be corrected within the 60-day window.
Conclusion
As you can see, submitting an NDA is no small feat, but with the right information, tools, and teams, you can set your product up for success. If your team needs operations support, whether it's planning and managing a successful preNDA/BLA meeting or building your eCTD NDA/BLA submission, The Sugar Water Operations Team is here to help. With over twenty years of experience, we're ready to be your operations partner in the "cubicle next door." Contact us to discuss how we can work together.