Difference between "misuse" and "off-label use"

[FoGia]

Hello,
Annex XIV to the MDR states the following:

The PMCF plan shall specify the methods and procedures for proactively collecting and evaluating clinical data with the aim of: [..]
identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct.

As anyone an idea why a distinction is made between misuse and off-label use? Are those terms referring to different concepts?

 

[planB]

Here is an (albeit pharmaceutical) definition by EMA in section 5.2.6 - quote:

In line with GVP VI.A.2.1.2 off-label use relates to situations where the medicinal product is intentionally used for a medical purpose not in accordance with the authorised product information. The focus is on the intention of the healthcare professional to use a product outside the authorised conditions of use. [...]

In line with GVP VI.A.2.1.2 misuse relates to situations where the medicinal product is intentionally and inappropriately used not in accordance with the authorised product information. The focus is on the intention of the patient or consumer to use a product outside the authorised conditions.

 

[Zero_yield]

As a loved one of mine was recently diagnosed with ADHD, I actually have a decent example for each of these.

Off-label use: Wellbutrin / bupropion is a medicine intended to treat major or seasonal depression. Some people with ADHD gain some benefit from it. However, there are only a limited number of studies supporting its use in this way, and many of them involve small sample sizes or have other asterisks. It's a safe enough medication that it's sometimes prescribed to treat the symptoms of ADHD, but Bausch doesn't make any claims about this.

Misuse: THIS IS SPAM - PLEASE REPORT THIS POST is a stimulant with proven effectiveness at treating ADHD. However, people sometimes abuse it for performance-enhancing effects or recreational purposes.

 

[FoGia]

While an interesting perspective (mention of the "medical purpose", "intention", "abuse") I don't see how these concepts could be well articulated with the MDR and more specifically with ISO 14971.

 

[Tidge]

While an interesting perspective (mention of the "medical purpose", "intention", "abuse") I don't see how these concepts could be well articulated with the MDR and more specifically with ISO 14971.

I think there are different approaches that can be taken. The following is what I would recommend as a first pass, for medical devices (per 14971)

"Off-Label Use" implies (to me) that the device is still being used as designed, but possibly as a treatment or therapy that is not supported by clinical studies, user validation, or otherwise cannot be guaranteed as "safe" (in the 14971 sense) The product labeling/IFU should be derived from the greater design effort (including risk management) so I think concerns around understanding "off-label" use are pretty well understood.

"Misuse" falls more into the general category of usability and should be considered as part of those efforts. Much like any analysis of failure modes, it is impossible to predict all of the potential misuses of a medical device, but a robust usability analysis will likely consider misuses in the areas of rule-based error modes, knowledge-based error modes, inattention, etc. My recommendation is to support those sorts of analysis in a document like a Use Failure Modes Effects and Analysis as a subordinate document for a Hazard Analysis... which ought to be fully compliant with 14971.

 

[blackholequasar]

I use a medication that is for seizures that also has a proven record in helping nerve pain caused by neuropathy. This is an approved off-label use, which is not abusive in nature. In fact, without it, I cannot walk. However, the drug can also be abused and has been documented as such which requires identification when purchasing it.

I guess what I am wondering is ... is that the responsibility of the drug manufacturer? To ensure that people use it effectively as an off-label product or that people do not abuse it (such as they do with opiates)? Or is that owness on the doctors who provide this?

 

[Ed Panek]

I have been prescribed an antihypertensive beta-blocker for stage fright during presentations. I had to present in front of 75 people on a topic I once knew well but no longer did but I knew more than any other members. This caused anxiety. My DR prescribed me 5 tablets of a beta-blocker off label.

I did not feel high or dull as I would be with a Benzo so it was perfect. Dry mouth, rapid heart, and elevated blood pressure didn't happen and it went well.

 

[Tidge]

Since this is in the context of medical devices (and not pharmacopeia) maybe we should try to bring some medical device examples.

Off-label use: In the pandemic era, ECMO has become a treatment for severe case of lung damage/loss-of-function for SARS-CoV-2 infections, yet relatively few of the devices used in ECMO formally had ECMO as an "on-label" use. Mechanically, many of the devices were always designed to be used for such long periods of time (pumps) while other elements (e.g. tubing) have physical limits on duration of use.

Misuse: A home-use therapeutic heating/cooling pad could be designed for a specific therapy, but a user may have the mistaken belief that the device could be used in some (potentially dangerous) circumstance... such as being used to keep an infant warm/cold.

 

[Ed Panek]

A printer that produces 14X17 images on film. Surgery planners would "Stitch" the images together for surgery planning for long bones such as leg operations. The images were 1 to 1 size reproduced on film. We found out about it after a field call at a surgery center and they had taped the images together and used it as a guide to performing surgery although that was never an indication of our printer. That's off label use.

An example of misuse is using a nonspecified printer without the proper DMAX and DPI to try to interpret mammogram images. There are specific requirements on lightboxes and softcopy monitors for mammo images to look for micro calcifications. I'm not sure what FDA would do in that case but it would result in numerous misses of breast cancer.

The legal and regulatory impact of digital mammography — Welcome to Breast Imaging Specialists (BIS) (mammobis.org)

"Printers should be dry laser, with a Dmax of 3.5 or greater, a base plus-fog level of less than 0.25, and 16-bit images with at least 12-bit gray levels. They should support true-size printing, and images should be justified so that the chest wall is printed as close to the edge of the film as the printer server is capable. Monitors must be 5K to achieve the resolution required for mammography images. "

 

[dgrainger]

I can't find a definition for 'off-label' use in a formal device context and for many low risk devices, there is no labelling to be on or off-label!

'Misuse' was defined as "misuse is intended to mean incorrect or improper use of the medical device." in ISO 14971:2007 but in newer versions only "reasonably foreseeable misuse" is defined.

IEC 62366-1:2015+A1:2020 has more on this plus consideration of Normal use, Correct use and Abnormal use.

I think the intention is for you to look at those events that fall outside your Annex I(3c) risk assessment.