Are CLINICAL DATA valid if not obtained according to local legislation?

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February 2017

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The real case is: A medical device is already long time on EU market and serving well to patients. Post market clinical follow-up have been performed and it delivered a lot of new clinical evidence which has been used in technical file of the medical device. Than, the EU member state competent authority found out that the original clinical trial has not been approved by them (in accordance with local legislation based on MDD 93/42/EEC). The competent authority is pushing relevant notified body to withdraw the certificate.

Question for discussin: There is no doubt that the manufacturer has breached the local act and should be punished for that. But what about validity of the clinical evidence?
a) Do you think that the original clinical data (assuming that scientifically and ethically correct) is not valid?
b) Do you think that other clinical data obtained during PMCF is also not valid?
c) Is there any precedent in EU, how competent authorities are solving such issues?

Thanks for your ideas. I believe that someone may have experience with such manufacturer`s fault to share for interesting discussion within the group 🙂

Ales

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Posted by Ales Martinovsky

Asked on February 19, 2017 12:00 am

83 views

	Private answer G M Butcher Based on your statements, and since you are asking for 'opinion'; a. It should be valid, b. It should be valid, c. not aware of any. If the CA is proceeding correctly under MEDDEV 2.7/2 revision 2, I would not understand why a summary certificate withdrawal is desired by the CA. The various sections of MEDDEV 2.7 reference many communication steps. Marked as spam Report spam
	Private answer Julie Omohundro The validity of any data is determined by the study design and data analysis, not by regulatory approval. The regulatory challenge is how to enforce approval requirements. This is problematic in any jurisdiction where the only enforcement tool is withdrawal of approval/certification. If the CA/NB want to keep the product on the market, the only alternative to immediate certificate withdrawal of which I'm aware is to require completion of a second trial in compliance with local law within a relatively short period of time. The data from the unapproved trial could be treated like any other clinical data available (eg, in published articles) at the time a clinical trial is designed, so that enrollment and follow-up requirements might not be as aggressive as for the original trial, when fewer clinical data were available. But I think this is at the discretion of the regulators. Marked as spam Report spam
	Private answer Ales Martinovsky Thanks a lot for your insights. In case that there are no precedents or court decisions available, we would probabaly keep the schisma and disunity here: Yes, data is most probably scientifically valid - but - how to enforce this opinion through NB... when the NB is acting under preasure of local CA (which is angry because of the original clinical trial infringement). Marked as spam Report spam
	Private answer Julie Omohundro I don't think you are in a position to enforce anything through the NB or otherwise. You could even be dealing with an NB that the CA is unhappy with for a lot reasons and may be considering withdrawing its designation altogether. There seems to be a lot of that going around lately: https://www.emergogroup.com/blog/2017/01/swiss-competent-authority-weighs-medical-device-firms-orphaned-their-notified-bodies Marked as spam Report spam
	Private answer Julie Omohundro As for precedent, there may be some, but because of the lack of transparency in the EU, the information is unlikely to be publicly available. . Marked as spam Report spam
	Private answer The question is "valid for what purpose?" I can only answer as a statistician whose interest is in scientific integrity(including data integrity) of medical research. If the post-market follow-up data were obtained under the false pretense of an already-approved product, and the original clinical data was submitted without local authority, then those data cannot be relied upon for resubmission purposes, no matter how compelling. There are steps that Sponsors must go through to ensure that humans aren't exposed unnecessarily to risks of experimental treatments. The medical device regulation exists for a reason. This Sponsor broke their obligation to public safety by sidestepping local regulation. They should not be allowed to use data that sidestepped those safeguards. Imagine a drug trial that collected data without IRB approval. Marked as spam Report spam
	Private answer Julie Omohundro Doug, ethical integrity and scientific integrity are separate issues, and the one does not affect the other. I haven't been following FDA's handling of these types of situations for a long time now, but once upon a time, I could say with some confidence that I had never seen FDA take punitive action against good data due to ethical violations in the way it was collected. That's because there is a flip side to that ethical coin. If the data are scientifically valid, and they show that the product will benefit patients, withholding it from the market also raises ethical questions. I come back to a key difference between the EU and US. The EU's only real enforcement tool is withdrawal of certification. FDA has a whole toolbox of enforcement tools at its disposal, so it can make life miserable for companies and/or clinical investigators in a number of ways, without having to deprive patients of a product supported by scientifically valid data. Marked as spam Report spam
	Private answer Lorenz Runge The key is, if a CA/NB "wants" to keep product on market. a) It´s for me clear that the data of the clinical trail are not valid for CE marking, because the trial had not been correctly approved by CA. You may ask the CA to get this retrospectively approved, but then the question of "wants" will take place. b) PMCF data should be valid for CE marking. c) I remember a case out of 2013 where a university start up in scandinavia missed the formal approval for their clinical trial due to uncertainty of the regulation. During CE marking process of their II.4 project it turned out that the clinical trial (very positive patient outcome) had not been approved by local CA. The local CA was not willing to give a retro approval, as the legal manufacturer was not in the same state where the clinical trial had been performed. The NB was not willing to CE mark without support from local CA. Consequently: End of II.4 process, end of this project, end of start up company. Marked as spam Report spam
	Private answer Manuel Saccani The information is contained in the MEDDEV 2.7.1 Rev.4 (june 2016).. This is the last edition of guide line Marked as spam Report spam
	Private answer Ales Martinovsky Thank you for all valuable comments. It seems to be overall result of all the posts that attitute and position of CA towards the case is the key. As Lorenz posted, if CA "wants" to keep the product on the market or not. - If yes, the way could be found: A lot of PMCF data exist, some gap analyses could be conducted, missind data completed and things could be - more less quickly - fixed... - If no and CA would raise concern about validity od ALL the data available, the manufacturer/sponsor is in major trouble and things are even worse by application of the MEDDEV 2.7.1 rev. 4 [for example look at 9.3.1 b), last paragraph and example provided in appendix A6 g)]. Thanks Manuel for the remark. Ales Marked as spam Report spam

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