Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

Hi all, 
we had our annual surveillance audit of the technical file and the clinical reviewer raised some questions on the validity of some of the criteria used in our clinical trials (how the study was powered, the validity of some clinical scales we used, etc.). He also raised some questions on whether our data substantiate our broad indications for use. However, both clinical studies and indications for use were previously reviewed by another reviewer during our transition to MDR (almost 2 years ago) and no problems were raised at that time.
Can NBs change their opinion and aks to narrow down the indication a posteriori, although data were previously approved? I know that FDA can't change opinion on something that has already been agreed upon, unless there is new scientific evidence. Is it the same with NB in EU? What is the best way to push back to these requests?
Thanks

Good day Anon,

Sadly, we have been experiencing and hearing about this time after time after time after time ... sighs.  Groups like the US FDA and many other regulatory agencies, the reviewers and personnel are trained similarly, review information similarly, and they can still query on new items though it is rare.  We have seen subsequent reviews done by Notified Body during surveillance audits and clinical audits where a different reviewer is calling information into question indeed where it has already gone through a "thorough" review process.  It has also been seen where the Notified Body administrative and supervisor also do not support decisions or reviews which had already been done in the past.  If they were incremental, that would not be too much of an issue because this is normal during a review especially if there are changes made by the organisation over time.  But we see drastic and major observations being raised subsequent to the initial EU MDR - and even seeing this during EU MDD update reviews.  Crazy.  The only suggestion is to discuss with the reviewer, question why issue is being raised now, elevate to their supervisor getting them involved, and use your awesome negotiating skills.  If not happy with what is being questioned after, personally I would raise this to the accreditation body of the Notified Body.  The simple answer is no, if they already approve something - it should be approved.  If the company makes changes, then maybe they could change their opinion.  Unless more companies complain to the accreditation bodies, this is not going to get better.  In fact, with the Implementing Act and the "plan to make it better" now Notified Bodies are only going to be reviewed every 5 years which is going to make it even worse with minimal oversight.

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Richard Vincins ASQ-CQA, MTOPRA, RAC
Vice President Global Regulatory Affairs
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Original Message:
Sent: 27-Apr-2023 08:18
From: Anonymous Member
Subject: Can EU NBs change opinion?

This message was posted by a user wishing to remain anonymous

Hi all,
we had our annual surveillance audit of the technical file and the clinical reviewer raised some questions on the validity of some of the criteria used in our clinical trials (how the study was powered, the validity of some clinical scales we used, etc.). He also raised some questions on whether our data substantiate our broad indications for use. However, both clinical studies and indications for use were previously reviewed by another reviewer during our transition to MDR (almost 2 years ago) and no problems were raised at that time.
Can NBs change their opinion and aks to narrow down the indication a posteriori, although data were previously approved? I know that FDA can't change opinion on something that has already been agreed upon, unless there is new scientific evidence. Is it the same with NB in EU? What is the best way to push back to these requests?
Thanks

All reviews are done with the experience of the ones doing reviews. They do make mistakes and sometimes they miss important information.

The first question has to be, "What is the risk?". You need to consider that under the EU MDR, the Notified Body bears some responsibility (and risk) for your product being placed on the market. This allows them to ask questions after the fact.

We all know that a key is to work with the Notified Body (and they still answer to the Competent Authority) and communication should be the focus. If the concerns are legitimate, you will have to address them to ensure the risk is acceptable (benefit outweighes risk). If this is an opinion of a single reviewer/auditor and the risk is acceptable, work with your scheme manager and follow the appropriate appeal process.

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Regards,
Mark Swanson, ASQ CBA, CMQ/OE, CQE ASQ, MBA
Becker MN
United States
------------------------------

Original Message:
Sent: 27-Apr-2023 08:18
From: Anonymous Member
Subject: Can EU NBs change opinion?

This message was posted by a user wishing to remain anonymous

Hi all,
we had our annual surveillance audit of the technical file and the clinical reviewer raised some questions on the validity of some of the criteria used in our clinical trials (how the study was powered, the validity of some clinical scales we used, etc.). He also raised some questions on whether our data substantiate our broad indications for use. However, both clinical studies and indications for use were previously reviewed by another reviewer during our transition to MDR (almost 2 years ago) and no problems were raised at that time.
Can NBs change their opinion and aks to narrow down the indication a posteriori, although data were previously approved? I know that FDA can't change opinion on something that has already been agreed upon, unless there is new scientific evidence. Is it the same with NB in EU? What is the best way to push back to these requests?
Thanks

I'm going to offer a slightly different perspective than some of the below, because the question mixes a number of points that I will try to unpack here.
First, broad claims that are being challenged later. Notified bodies can change their views on a device and under the MDR they also must if the clinical data of the manufacturer does not keep matching the state of art over time in light of what is claimed. In this exposé of facts we are missing things that I routinely see clients not get right, such as wanting to base 'broad indications' (people always want broad indications) on the thinnest slice data possible (not saying that this is the case here) but are less enthusiastic about putting in place the PMCF necesarry to check if these broad claims remain substantiated over the lifetime of the device as is required. My recommendation is always, invariably, that that with great broad indications comes great PMCF responsbility, because if you don't falsify your broad indications yourself, the notified body may do this at some point if it does not see PMCF data to match and there are some questions about the quality of the starting data. More often than not when a client experiences a notified gnawing at this indications, this is possible because they have no PMCF data that supports the initial broad scope. The best favor you can do yourself as a manufacturer with broad claims is to PMCF the sh*t out of these broad claims (Marc Whatney would say), so you'll be able to support them when the notified body questions them, which the notified body is supposed to do. Yes, that takes more time and resources unfortunately, the burden of a broad claim under the MDR - you have to be able to support it in its entire scope over the entire lifetime and do the work needed for this. 
Secondly, in the facts here the notified body raises ex post doubts about the quality of the data because of its suspicion of potential shortcomings in the trial design and execution. The fact that this was perhaps the first time doesn't mean that a trial with shortcomings is OK. You want this to be possible because you do not want devices on the market based on faulty trials. If the design of the trial was good, and the trial devices were properly calibrated, then there should be no issue in refuting this. A responsible manufacturer with a good CRO has the data at his fingertips for this.
I'm not a US law expert but I'm pretty sure the FDA can get back on a licensed scope of use of a medical device if the underlying data were obtained in a clinical trial that retrospectively did not meet let say GCP requirements. My question would be what the 'agreement' referred to would be. Anon's question mixes up what seems FDA agreement on scope of indication and notified body doubts about the proper execution of a trail AND agreement on scope. This is comparing an apple with a hybrid apple/orange - still not the same.

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Erik Vollebregt
Partner
Amsterdam
Netherlands
------------------------------

Original Message:
Sent: 27-Apr-2023 08:18
From: Anonymous Member
Subject: Can EU NBs change opinion?

This message was posted by a user wishing to remain anonymous

Hi all,
we had our annual surveillance audit of the technical file and the clinical reviewer raised some questions on the validity of some of the criteria used in our clinical trials (how the study was powered, the validity of some clinical scales we used, etc.). He also raised some questions on whether our data substantiate our broad indications for use. However, both clinical studies and indications for use were previously reviewed by another reviewer during our transition to MDR (almost 2 years ago) and no problems were raised at that time.
Can NBs change their opinion and aks to narrow down the indication a posteriori, although data were previously approved? I know that FDA can't change opinion on something that has already been agreed upon, unless there is new scientific evidence. Is it the same with NB in EU? What is the best way to push back to these requests?
Thanks