Regulation vs. Guidance

Above image borrowed from this presentation by Steve Wilson of FDA (where it was originally credited to S. Woolen)

Looking online, one can find a lot of information regarding regulatory submissions standard strewn about. Whether from the ICH, FDA, EMEA and its member authorities, or beyond, there is tons of information out there. In general, we can group information from the authorities into two tiers: Regulations, and Guidance.

These two terms themselves carry some connotation as what the differences are, but a problem I have observed is newcomers to submissions (and eCTD specifically with all of it's new technical components) often get the two confused, and will go to great lengths to comply exactly with Guidance. Regulations on the other hand, must be complied with in order to allow the agency to review your submission. In some cases they are technical (i.e. to ensure that your eCTD XML file can be properly read and reviewed), in other cases reviewers have submission processes in house that are powered by prerequisites established in regulations. Failure to comply with regulations can (in the best case) result in approval delays or (in the worst case) a Refusal to File.

As the above picture illustrates, in most cases guidance points to best practices that will make life easier when it comes to submission prep for the sponsor, or reviewing procedures for the reviewer. I have heard inquiries indicating that a sponsor is going to to great pain for what might not be a requirement in the eyes of the reviewer.

In one extreme case, a company had inherited (through an acquisition) a selection of legacy study reports that would be submitted as part of a marketing application. Seeing a guidance document that mentioned that non-scanned, ICH E3-formatted reports are prefered, they were prepared to generate OCR copies, paste the OCR text into Word, QA and spellcheck the OCR results, redefine headings and section breaks, redistill to PDF and re-bookmark and hyperlink. Although this might ultimately produce nicer copies, the potential for errors and time-crunch would have far-outweighed the benefits from an effort and resource perspective.

So, how do you know which side to err on in an individual case? There are a number of options. First, most agencies will hold pre-submissions meetings. Doing a gap analysis based on current guidelines and the state of your submittable documents will help you know what the issues are, clearly illustrate them to the reviewers, and get their opinion. If issues come up later and you have missed this opportunity, leveraging a capable eCTD submissions partner who can ask these questions anonymously on your behalf or leverage their experience and opinion across multiple sponsors might be worth its weight in gold.