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not having regulatory clearance

  • 1.  not having regulatory clearance

    Posted 22-Sep-2020 11:19
    Hi
    Can somebody help me out. Is there a difference in: "not having regulatory clearance" and "Off-label use".
    From me personal logic I would say there is no difference, but I might be missing something here.
    Thank you for your help in advance.


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    Stefan Maartense
    MD, PhD
    Amsterdam
    Netherlands
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  • 2.  RE: not having regulatory clearance

    Posted 22-Sep-2020 14:24
    At least in the US there might be a difference - not having clearance would effectively imply to me that you cannot sell the subject product for any purpose whatsoever.  Off-label use is where you have a product cleared for sale for one indication but that someone has decided to use for a different purpose.  That can be legal if that is done in the practice of medicine because the US FDA does not regulate the practice of medicine so once a product is cleared for marketing for any indication then a healthcare provider can legal use it for any indication that they consider effective.

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    Victor Mencarelli
    Global Director Regulatory Affairs
    MelvilleNY
    United States
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  • 3.  RE: not having regulatory clearance

    Posted 22-Sep-2020 15:11
    This is an official interpretation from Health Canada regarding "off-label use".
    https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/notice-statement-investigational-use-marketed-drugs-clinical-trials.html
    I hope it helps.

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    Sorin Alb RAC
    Project Manager, Regulatory Affairs
    Scarborough ON
    Canada
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  • 4.  RE: not having regulatory clearance

    Posted 22-Sep-2020 20:20
    To me this can get a little snarly when people think device = contraption.  If by "device" you mean contraption plus intended use, then, yes, not for any intended use whatsoever, but there is really only one intended use at issue, because if the contraption were cleared for a different intended use, then that would be a different device.  But if you think in terms of device=contraption, the same contraption could be cleared and sold for another intended use.

    To me, the key is cleared is about what you can market it for, while "off-label" is about what physicians can use it for, and the two are independent from each other.

    ------------------------------
    Julie Omohundro, ex-RAC (US, GS), still an MBA
    Principal Consultant
    Class Three, LLC
    Mebane, North Carolina, USA
    919-544-3366 (T)
    434-964-1614 (C)
    julie@class3devices.com
    ------------------------------



  • 5.  RE: not having regulatory clearance

    Posted 23-Sep-2020 03:50
    Hi thanks for you swift reply. In this case it is about the use of medical devices in the US. We have a discussion on whether a certain usage/surgical procedure is off-label, since it is not in the indications.  But some colleagues are of the opinion that the indications could imply the use of the device in that way, so it would not be off-label, only not having regulatory clearance? Especially since the procedure is not mentioned as a contra-indication. 
    This seem to be a very grey area, if we interpret it this way, in my opinion. Or is this grey area allowed for US FDA? It makes for example handling of complaints a lot vaguer adding a third category "not having clearance"? It is not allowed for EU-MDR, there indications have to be very specific and data has to be provided to show safety and performance.

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    Stefan Maartense
    MD, PhD
    Amsterdam
    Netherlands
    ------------------------------



  • 6.  RE: not having regulatory clearance

    Posted 23-Sep-2020 09:32
    Edited by Julie Omohundro 23-Sep-2020 09:38

    There is a long history with FDA regarding off-label use.  FDA's perspective and interest has waxed and waned over the years.  Not sure where it stands right now, except generally on shaky ground, sigh.

    To me this is about the data that you have to support your claims and the level of risk your device poses to patients when used "as intended," meaning for the use that you claim it is good for.  It can be easier to get a device through FDA for general surgical use than for a specific use.  That is because, for the former, you just need data that support its use for "whatever."  For example, you conduct a clinical trial in which the device is used for whatever surgery the surgeon wants to use it for.  (Think suture.)  The trial results will most likely reflect safety and effectiveness across a range of procedures combined.

    Now consider what happens if you advertise for a specific use.  Then more surgeons will start to use it for that type of procedure.  It may turn out that the device is more or less safe or effective for that particular procedure than for the range of procedures included in your trial.  (This is why I say "average" can be used to cover a variety of sins.)  FDA's concern is, of course, that it might be less safe or effective.  In that case, you are encouraging more surgeons to expose more patients to a device that is higher risk for those patients, than for the general surgical patient population, and without adequate data to determine how safe and effective it might be.

    I think this is a gray area.  The surgeons are not actually using it "off-label," because the label is for whatever, and that essentially means any and all types of procedures.  However, if you are in any way encouraging a specific use, then FDA may decide are marketing it for an uncleared use, because your clearance is for general use only.

    The other situation is that you already market it for one or more specific uses and surgeons are using it for specific use that is not one of those specific uses.  Then they are clearly using it off-label. If you are in any way encouraging a specific use that is not one of the specific uses that is covered by your FDA clearance, then you are being very, very bad. :)

    Another gray area is determining what behaviors you might engage in that FDA could decide are "encouraging" off-label use.  Here is where there has been some waxing and waning over the years.  Sometimes off-label use is a hot button for FDA, other times, not so much.  At some point, it stretched to something like "if it could be reasonably inferred that your device could/would be used for (maybe even "more often"), then you were on the hook for that intended use, I guess on the theory that, merely by marketing it for surgical use, you were really marketing it for that specific use.  (I have seen at least one device for which this was clearly the case, although FDA never made a fuss about it, probably because it was so safe as to be boring, and had established that track record at a time when off-label use was not a hot topic with FDA.)

    Finally, things got a bit murkier still (IMO) when FDA decided (or was made to understand) that, even though you couldn't "encourage" off-label use, if surgeons were using your device off-label, their patients would be better served if you shared whatever data and information on that specific use you might have.  This moved the line, which was previously drawn between "encouraging" versus "not encouraging," to between "encouraging" and "informing," which I think is a lot fuzzier.   Loosely put, it seems to have settled out that, if you only provide information if a physician asks, you are "informing."  If you provide information that the surgeon has not requested, you are "encouraging."

    Perhaps more than you wanted to know, but it took me forever to work all this out in my head, so I share it now and then for anyone who might be trying to work this out for themselves.  Of course, I could be totally wrong, but it's at least a conceptual model that has made things less murky for me (or at least made the murkiness clearer to me, LOL) and has so far not led me wrong.

    And now maybe some folks here who have grappled with the murk more recently than I have can clarify where I'm wrong and also update you as to where FDA is these days, on its waxing and waning.



    ------------------------------
    Julie Omohundro, ex-RAC (US, GS), still an MBA
    Principal Consultant
    Class Three, LLC
    Mebane, North Carolina, USA
    919-544-3366 (T)
    434-964-1614 (C)
    julie@class3devices.com
    ------------------------------



  • 7.  RE: not having regulatory clearance

    This message was posted by a user wishing to remain anonymous
    Posted 22-Sep-2020 16:54
    This message was posted by a user wishing to remain anonymous

    A Class 1 device would not have regulatory use, but it could be used completely for what it is intended for. As well, de novos are granted, not cleared, and premarket approvals are approved, not cleared. Article on the topic:

    https://www.greenlight.guru/blog/fda-clearance-approval-granted


  • 8.  RE: not having regulatory clearance

    Posted 22-Sep-2020 21:18

    Hi ,

    Drugs must be approved by USFDA for it be marketed within US. However here are a few  exceptions. (examples are; if it falls under GRASE category or a drug with ongoing DESI review proceedings.)

     A physician can prescribe an approved drug for an unapproved indication aka-Off-Label Use. This off label use/prescription is allowed only if the drug is legally marketed in the country.

    Drugs marketed with no regulatory clearance are considered illegal and cannot be prescribed or used on patients.

    For drugs that have open INDs, a physician can leverage the expanded access program in patients with immediate life-threatening conditions.

    Regards,



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    Shilpa Pillai
    Naperville IL
    United States
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  • 9.  RE: not having regulatory clearance

    Posted 22-Sep-2020 23:24
    "This off label use/prescription is allowed only if the drug is legally marketed in the country."

    Who allows it?  I'm of the same mind as Victor, that FDA does not regulate the practice of medicine.  As far as I know, physicians are free to use anything they can get their hands on to treat their patient, at least as far as FDA is concerned.


    ------------------------------
    Julie Omohundro, ex-RAC (US, GS), still an MBA
    Principal Consultant
    Class Three, LLC
    Mebane, North Carolina, USA
    919-544-3366 (T)
    434-964-1614 (C)
    julie@class3devices.com
    ------------------------------



  • 10.  RE: not having regulatory clearance

    Posted 23-Sep-2020 04:53
    Hi Stefan,

    I have had these discussions over the years (often over a couple bottles of wine!) discussing ways products are placed on the market and/or interesting ways to get products on the market in different countries.  By you saying not having regulatory clearance assuming you are talking about 510(k) clearance through the US FDA.  For me this is quite clear.  If you do not have a valid 510(k) clearance (or PMA Approval or properly registered device) then you can not place the product on the market.  Some get around this by saying research or investigational use only - but then you need to have a clinical trial protocol, IRB, informed consent, etc. or for research should not be used on humans.

    The difference for me on the off-label use is there is a valid 510(k) clearance or PMA approval or even a Class I device properly registered, but the device is being used for some other indication.  Off-label use means exactly that: the IFU has an indications for use/intended use statement for the device's normal intended purpose.  These are valid approved or cleared medical devices being used for some other purpose.  As an example, there may be a screw and plate system with an indication for use on long/short bones in the extremities.  An off-label use would be a physician using the screw and plate system say for cranial applications.  While some would argue medical practice allows physicians to treat patients, and others would argue the IFU does not say it can not be used for cranial applications, but a regulatory authority would most likely have a different opinion.  The screw thread size may be appropriate for a thicker radial type bone and would not hold the same in a more flat bone in the cranium.

    So while medical practice is quite important as Victor mentions, the FDA still has the responsibility for the health and safety of patients in the United States - as well as many other regulatory authorities or Health Ministries around the world.  If a device is not being used for the intended purpose and there could be a safety concern, as mentioned in the example, as the Manufacturer it is responsibility also to ensure devices are safe and effective/performs for their intended use.  If a physician is using your device in practice of medicine, you become aware, and the device could have a safety concern then a contraindication may be needed or the company needs to go through the regulatory process to obtain the "new clearance" for the different indications for use or the so-called off-label use.

    Yep, it is a grey area - why nice discussion sipping your choice of beverage usually able to talk through the different scenarios !

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    Richard Vincins RAC
    Vice President Global Regulatory Affairs
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  • 11.  RE: not having regulatory clearance

    Posted 23-Sep-2020 06:11
    Thank you! I agree with you, you worded our/ my concerns in the third paragraph.

    ------------------------------
    Stefan Maartense
    MD, PhD
    Amsterdam
    Netherlands
    ------------------------------



  • 12.  RE: not having regulatory clearance

    Posted 23-Sep-2020 09:06
    The US FDA has some guidance on what is expected of manufacturers when physicians have found an interesting way to use their equipment.

    Labeling: Regulatory Requirements for Medical Devices
    "If a manufacturer knows or has information indicating that his device is to be used for conditions or purposes other than those for which it was intended, he is required to provide adequate labeling in accordance with such other uses. (An example of this might be a manufacturer of dental X-ray equipment who is routinely selling his product to podiatrists.)"

    https://www.fda.gov/regulatory-information/search-fda-guidance-documents/labeling-regulatory-requirements-medical-devices-fda-89-4203

    General/Specific Intended Use: Guidance for Industry
    "the principles used by FDA to determine whether the addition of a specific indication for use to a medical device cleared for marketing with a general indication for use could trigger the need for a PMA."

    https://www.fda.gov/regulatory-information/search-fda-guidance-documents/generalspecific-intended-use-guidance-industry


    ------------------------------
    Anne LeBlanc
    Manager, Regulatory Affairs
    United States
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  • 13.  RE: not having regulatory clearance

    Posted 23-Sep-2020 10:24
    I believe that the amendment posted yesterday changes what Anne quoted.

    https://www.fda.gov/news-events/press-announcements/fda-clarifies-types-evidence-relevant-determining-intended-use-fda-regulated-products?

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    Pamela Stogsdill
    Regulatory and Quality Specialist
    Oak Creek WI
    United States
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  • 14.  RE: not having regulatory clearance

    Posted 24-Sep-2020 06:15
    Look at the new proposed Rule on intended use to see if this Guidance  will change about what a manufacturer has to do.

    I did not have time  yesterday to dive in. Has anyone?


    ------------------------------
    Ginger Cantor, MBA, RAC
    Founder/Principal Consultant
    Centaur Consulting LLC
    River Falls, Wisconsin 54022 USA
    715-307-1850
    centaurconsultingllc@gmail.com
    ------------------------------



  • 15.  RE: not having regulatory clearance

    Posted 24-Sep-2020 06:12
    Interesting discussion,  but you may want to look at FDA's proposed rule on intended use, up for comment through Oct 23.  It published in the Federal Register this week.  They are publishing it to "clarify " intended use, including off-label use and whether the manufacturer knows about off-label use......

    Be sure the comment, as the public period is short. Also, ironic this came out 2 days after Alex Azar said only he as head of HHS, and not FDA, could  promulgate Rules.

    ------------------------------
    Ginger Cantor, MBA, RAC
    Founder/Principal Consultant
    Centaur Consulting LLC
    River Falls, Wisconsin 54022 USA
    715-307-1850
    centaurconsultingllc@gmail.com
    ------------------------------



  • 16.  RE: not having regulatory clearance

    Posted 23-Sep-2020 10:39
      |   view attached
    I managed design controls for IDE research at the Cleveland VA. Surgeons were required to wrap a nerve "cuff" around nerve bundles in the upper arm. For practice, cadavers were used and surgeons used already existing surgical tools to help wrap the cuff around the nerve bundle and wrote this into their surgical plan. I have attached an image of what it looked like after surgery using a model

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    Edward Panek
    VP, QA/RA
    Blue Spark Technologies
    Research into Neural Nets - https://www.twitch.tv/edosani
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  • 17.  RE: not having regulatory clearance

    Posted 23-Sep-2020 16:28
    Thank you, @Pamela Stogsdill !

    They've put considerable effort into proposing a ​​​small clarification for this interesting grey area.

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    Anne LeBlanc
    Manager, Regulatory Affairs
    United States
    ------------------------------