This post will address the RTR/RTF SOP issued by FDA
and its nature. If you are interested in actual SOP language from the FDA's SOPP 8404, read below:
A RTR/RTF is a very political thing. Remember in the old days, applicants used to file applications, FDA would accept them for review, and then there would an endless cycle of deficiency letters, responses, new deficiencies, etc. In fact, some files went through years of review, answers, supplementation, etc. That is because applicants didn't pay big user fees nor did FDA have review targets.
Fast Forward: Congress mandates that FDA have goal dates/target action dates, etc. And the new statutes require a company to get a full complete response versus piecemeal reviews based on the underlying discipline. We know that when a company gets a CRL (complete response letters), investors get spooked into wrongfully thinking that the FDA has categorically and finally rejected the file (that is, the file will never get approved), and finally disapproved. Not the case. The CRL simply replaced the old deficiency letter (major, minor, telephone amendment) system. Also, congress has strict goal dates put in.
FDA's CBER SOPP 8404 clearly states that FDA will err on the side of issuing an RTF: "RTF is an important regulatory tool to help CBER avoid unnecessary review of incomplete applications and supplements. Incomplete submissions can lead to multiple-cycle reviews and inefficient use of CBER resources and may also delay the review of more complete submissions from other applicants."
Now, if the FDA has accepted a file for review, put it into the formal review queue, but then pummel the company with CRL's, it has two effects. First, the FDA can get tagged with not meeting its goal date; something the Commissioner has to answer for in its annual report to Congress. Remember, once FDA starts teh review because the file is accepted, the FDA clock starts. Also, it hurts the company because the nature of the CRL would be out of the blue.
Starting years ago and in fact FDA created new Guidance in 2017, that continues to tighten the incoming filing requirements so that the file is not even accepted. For FDA, this means the 6 month/10 month review clock doesn't even start because there is no file yet that is in queue. So by bouncing files at the outset, it tells the company that it needs to do some additional things. This is, in fact, a first review, albeit informal review. It tells the applicant that FDA wants X, Y, or Z.
I would rather have FDA tell me that first, versus hitting me with a CRL later on, when the market/investors/company is getting primed for approvals instead of rejections.
I can tell you that big and small companies get RTR/RTF's. BMS/Bluebird just one a RTF/RTR. Years ago, Roche got one on herceptin (which is now a multi billion dollar drug).
Why get a RTR/RTF? I have specific experience. Sometimes the data packet is not in the right form. For example, the file has line charts, but FDA wants bar charts and raw data tables. Sometimes, documents are submitted in the foreign language but no translation (believing that the translation was not needed per se or yet). I have seen foreign companies file in English, but it's bad English grammar (think Ching-lish, Ind-lish, Kor-lish). Other times, the data tables do not yet include the raw data or the methodology. These are correctable.
Other times, you see that the deficiency is major like not enough data, new patients needed, etc. Now, what's the likelihood that if CYDY was availing itself of the pre-submission meetings to understand what clinicals would be needed, that it didn't do the needed clinicals?
FDA's CBER SOPP 8404 states the various (general) reasons for a RTF, and you will see they are correctable:
"Policy A. RTF decisions are made on submissions that do not, on their face, contain information required under section 351 of the Public Health Service Act; the Federal Food, Drug, and Cosmetic Act (FD&C Act); or in the FDA regulations (e.g., § 601.2 for BLA and §314.50 for NDA). RTF decisions can therefore be based on findings such as:
(1) Administrative incompleteness, such as clear omission of information or sections of required information;
(2) Scientific incompleteness, such as omission of critical data, information or analyses needed to evaluate safety, purity and potency or provide adequate directions for use; and
(3) Inadequate content, presentation, or organization of information such that substantive and meaningful review is precluded, such as illegibility; failure to translate portions of the application into English; data tabulations (line listings) or graphical displays that are uninterpretable; failure to reference the location of individual data and records in summary reports; absence of protocols for clinical trials; omission of critical statistical analyses or the analysis of a study as planned in the protocol (as opposed to a different, post-hoc analysis)