I think many EU IVD manufacturers are currently struggling with the question how to be in compliance when they need venous blood collections for analytical performance studies. The 'old' way was to have an internal blood donor program, covered by Ethics Committee. Those blood specimens were used for the performance verification program.
But now IVDR forces any performance study in which surgically invasive sample-taking is done only for the purpose of the performance study into an Annex XIV submission requiring competent authority authorization. Most EU member states will follow (MDR Annex VIII, Chapter 1, 2.2) and concur that venipuncture is a surgically invasive sample-taking procedure. The Annex XIV submission procedure can however be very lengthy.
While waiting on the MDCG Q&A guidance document on performance evaluation studies (where this hopefully will be tackled), any ideas how to approach this? Any experience in being compliant but not having to go for performance evaluation study authorization? EU countries that handle Annex XIV submissions smoothly when prospective venipunctures are clearly used for analytical performance studies only?
Thanks, all feedback welcome!
I can tell you that in the UK such studies will require Ethics Committee approval only. I think this would be the case in the EU too but will leave the colleagues to comment on this.
It is important to clarify if the blood is collected specifically for the test or it is collected as standard of care and some of it used for the test. Based on this information the colleagues will be able to give you advice on EU requirements.
Have a great week,
You bring up an interesting challenge. It seems the quickest route would be to determine a study design where you could use leftover specimens for these studies. This would allow you to only require ethics review. You must also still respect data protection requirements for these leftover specimens.
I will say that you might find where some Member States take a different interpretation on whether venipuncture is considered invasive. Part of your due diligence might include specifically asking each MS CA where you're considering collecting specimens their interpretation of this.
Best of luck!
Thanks! Yes, left-over specimens are a good way out - but not for studies to establish specimen stability claims. For these particular studies it is also not possible to source commercially available specimens since this will rule out the option to test the zero timepoint...
Yes, some member states will have different interpretations on what is invasive. There are e.g., differences between Belgium and the Netherlands as to whether capillary collections are invasive. Of course, the problem starts if you have/had a company-internal blood donor program and the company is based in a member state that does consider venipuncture as surgically invasive...
not sure how other member states handled this previously, but as far as I remember the previous German law (MPG) also required authority authorization for performance studies involving invasive sampling performed exclusively (or in the MPG even to a substantial degree) for the study (MPG §24). Given the definition of "surgically invasive device" in Annex VIII MDR that you cite I also assume that it is improbable someone will interpret venipuncture as not surgically invasive.
With respect to submission procedure as far as I can see you will at least be able to go via the Article 66 (7)a route that should allow you to start the study after successful validation date instead of having to waith for the full authorization, but I know currently of no example how well that procedure worked.
yes that's true - at least for apparently healthy volunteers (and most patient groups) it would be possible to argue that the Article 66.7(a) route can be followed - with the caveat that ultimately it is BfArM that will decide if there is a significant clinical risk involved.
From what I hear, they can be reluctant to allow this route - but maybe it is a matter of properly explaining and framing the study.
Thanks for the feedback!
Hi Anon,Based on our experience, few EU countries including Italy will not necessarily consider blood collection by venipuncture as a "surgically invasive" sampling technique, in line with FDA approach on this (see In Vitro Diagnostic (IVD) Device Studies - Frequently Asked Questions, FDA guidance June 2010). It is true, however, that the procedure could be considered either invasive or generating "other risk" for study subjects, in which case IVDR Annex XIV procedures would still apply. I think a good approach would be to provide a rationale in the clinical performance study plan as to why the manufacturer believes that blood collection by venipuncture would not represent a risk for study subjects. Such rationale should take into account different aspects such as subjects involved in the study, quantity of blood to be collected, collection frequency etc. If the rationale is sufficiently strong, the manufacturer should submit the study only to the Ethics Committee (EC) and rely on its judgement. It would remain in the EC authority to determine if the study would also require CA authorization. This approach was successful for a study we recently followed requiring repeated blood collection from transplanted patients in Italy.
thank you for your message. But isn't it not up to the EC to decide if the study needs to go to the competent authority? They must of course issue a positive opinion first, but I didn't think they have the regulatory authority to decide whether or not the proposed study requires an 'annex XIV' submission. Am I seeing this wrong?
The requirements making this challenging are on the one hand how the sample is taken, on the other if the donor agrees for their sample to be used in a specific test. The IVDR does not describe what happens with left-over samples, and there is no MDCG guidance on this. Therefore, we can interpret the regulations ourselves. IVDR Article 58 mentions performance studies 'in which surgically invasive sample-taking is done only for the purpose of the perfomance study'. If we look at the case of left-over samples, they are taken from the fridge. I would not consider that surgically invasive (the fridge may have other thoughts, though).
Next is the ethical aspect. A donor may be asked if the sample can be used on multiple studies, but without knowing what these studies are, they don't know what they agree to. My slightly controversial recommendation would be that they agree for future samling under conditions:
This last condition should prevent a company from bending the first two rules.
If the authorities do not agree with this approach, this will either mean that it becomes too burdensom to have certain IVDs CE-marked, or more donors have to undergo this invasive sampling procedure and be therefore exposed to unnecessary risks.
Dear MDCG, what do you think about the above?
in fact, the IVDR does not specify which entity is responsible for deciding whether a IVD study should be submitted or not to the competent authority (CA) So, I am not sure that an EC would be entitled to do so but this is what I would recommend. Notably, this would also depend on the EU country involved and let's not forget that different CAs may have different opinions. In thos EU countries where the CA is accessible and responsive, the best option would be to ask them directly. In other EU countries, waiting for an answer from the CA would mean waiting for weeks or months and in this case my recommendaiton would be that the sponsor takes this responsibility and, in case of doubt, ask for CE opinion on the matter. I agree there's no perfect solution for this.
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