Your question doesn't seem to be asking how to derive/identify the appropriate warnings and precautions. Accordingly, I'll forego a discussion of that, as it seems out of scope. Instead, it seems that you're asking about how to arrange / format your known warnings/precautions in the IVD labeling; so, I'll focus on that.
For the medical device world and medical device labeling in general, and even more so regarding IVD device labeling, FDA has provided fairly prescriptive, informative instruction to us regarding its expectations for our attention to "warnings", "precautions", "contraindications", and adverse reactions in device labeling.
Specifically, FDA intends (see FDA's Memorandum #G91-1) that its device submission reviewers, and industry alike, approach these terms in a manner analogous to the way the terms have traditionally been used and labeled for drugs. Accordingly, your pharma background and instincts will serve you well in the scenario you've described.
Moreover, paring this with corresponding statutory/regulatory basis, I think it is relatively clear, and objectively so, that the warnings and precautions should not be embedded in the IVD "Results" section of the IFU, but are better instead to be featured separately. I explain further below.
First, I would echo Richard's mention of looking at the labeling of legally marketed competitive devices. That can be a very informative way to get hints about FDA's expectations (I demonstrate that below). But ultimately, a purer statutory and regulatory standpoint is the most authoritative way in my opinion. Overall, here are a few things for consideration that seem to give relatively clear direction on the matter of how we should format our IVD warnings and precautions in the IFU:
- In addition to the statutory/regulatory basis explained below, it is perhaps most notable that other U.S. Class III legally marketed cancer diagnostic IVDs contain the warnings and precautions in a separate dedicated section(s).
- For IVDs, the IVD labeling regulations in 21 CFR 809.10(a)(4) seem to require a dedicated section for the warnings (and also the precautions, contraindications, etc., per extrapolation of the reviewer/industry directives in Memorandum #G91-1). Although 809.10(a)(4) is for the content of the IVD "label", there are nonetheless certain exceptions to instead put the 809.10(a)(4) general IVD warning / precaution information in the "labeling" (e.g., IFU) rather than the label (yet per FDA guidance, evidently not the subset of 16 CFR Part 1500 warnings for hazardous substance handling).
- While Memorandum #G91-1 is only a guidance document, remember that the FDA reviewers will assert the principles therein as their means for enforcing the statutory requirements promulgated into the aforesaid 809.10 regulation, as well as those in Parts 807 (premarket notification / substantial equivalence) and 814 (premarket approval / safety / effectiveness).
- 809.10's section (b) for the IFU is quite strict regarding the format and order of the IFU. Moreover, it in addition demands that the required IVD IFU elements be stated only in "one place" in the IFU. Combining this with the G91-1 principles applied by FDA reviewers, it again seems most appropriate for us to have the warnings and precautions separated out under a respective header(s) rather than embedding them in sections designated for other purposes by 809.10(b).
- Remember also that, if the FDA doesn't like how you've arranged / formatted your IFU, then the agency will give you an opportunity to resolve this as part of the premarket review process. Assuming it is just an issue of layout, then such a request might reasonably not cause a submission hold. And to reduce submission risk and uncertainty even further, you can also propose a layout during pre-sub correspondence if that is part of your regulatory plan/schedule.
------------------------------
Kevin Randall, ASQ CQA, RAC (U.S., Europe, Canada)
Principal Consultant
Ridgway, CO
United States
© Copyright 2022 by ComplianceAcuity, Inc. All rights reserved.
------------------------------
Original Message:
Sent: 23-Nov-2022 02:15
From: Richard Vincins
Subject: Labeling (warnings and precautions)
Hello Anon,
Warnings and precautions in medical device labelling should be linked to your risk management process, specifically residual risks. This is a complicated and fairly mis-understood area on how risk control applies, information provided to the user, and what are considered residual risks. Depending on definitions and how applied, cautions also would not be residual risks, but only information for the user - such as something which came out of usability studies. Then it goes even over-board in the European Union where Notified Body reviewers/auditors want to see every risk listed in the Instructions for Use (labelling). Another approach to use also is state of the art to see what similar IVD devices or competitive devices are listing in their labelling, but use care because that may also not always be correct. In the medical device world, there is no prescriptive requirements for warnings, precautions, cautions such as in the pharmaceutical world because there is such a variety of products to consider and establishing a standardised warnings and/or cautions list would be a monumental task. Just make sure to use the risk management process for developing, linking, and disclosing risks associated with the device (and IVD devices have other considerations since there is no direct patient contact).
------------------------------
Richard Vincins ASQ-CQA, MTOPRA, RAC
Vice President Global Regulatory Affairs
Original Message:
Sent: 22-Nov-2022 12:23
From: Anne LeBlanc
Subject: Labeling (warnings and precautions)
Hello Anon
Normally you'll see a summary of general warnings and precautions at the beginning of the IFU, and specific warnings and cautions as applicable in each section. If you're thinking of trying an unusual layout, it could be especially important to cover that in the usability studies, to find out if the users are understanding what they need to understand.
Here's a helpful guidance with FDA perspective: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-medical-device-patient-labeling
------------------------------
Anne LeBlanc
United States
Original Message:
Sent: 22-Nov-2022 09:25
From: Anonymous Member
Subject: Labeling (warnings and precautions)
This message was posted by a user wishing to remain anonymous
Hello Experts,
I come from the Pharma side regulator and currently working on a new project; a class III IVD diagnostic for cancer. In my view, for our patient IFU the risk of erroneous results (i.e. false positive/negative) should be included in the warnings and precautions section. As of right now it's listed on its own page in the IFU under a section called "results" which go into what a positive mean, etc... and the test could give you false positive/negatives) .... Ultimately we are addressing the risk/harm factor there but in the drug world it has to be listed under "warnings and precautions", there are very strict labeling guidelines. I'm having a hard time taking off my drug hat here therefore wanted to get different opinions if you think FDA will accept this?
Thank you