Dr. M.Sc. Bassil Akra (BA), Director Clinical Centre of Excellence (cCE) at TÜV SÜD Product Service GmbH, was in Vancouver BC for a recent ISO meeting and took the opportunity to visit customers and ViVitro Labs.
ViVitro Labs and TÜV SÜD participate together on several ISO committee meetings with regards to standardization of cardiovascular devices. TÜV SÜD is the biggest notified body in the world that approves devices for the European market.
Rob Fraser (RF), Lab Manager, MSc. at ViVitro Labs, spoke with Dr. Akra about the differences in North American and European regulations. Here is a portion of their conversation:
RF: Are companies prepared for the new ISO 17025 requirements?
BA: ISO 17025 is not new and presents a method allowing acceptance of testing and calibration results over borders. This standard is used by accreditation bodies to recognize the competence of testing and calibration laboratories that operate in accordance with well-known quality management systems by complying with this standard.
Accredited test labs have the opportunity to market services globally because their test results are deemed trustworthy by international standards. It should be noted that this is just applicable in cases where labs obtain accreditation from bodies which have entered into mutual recognition agreements. This provides higher trust and easier market access.
For example, in Germany since approximately 10 years MPG § 15 (5) it is a requirement for notified bodies to involve recognized and accredited test labs when fulfilling their obligations. In cases where no test lab is accredited for specific test methods, we review the full validation report of the testing methods, challenge the methods and the obtained results and audit the lab to understand how the data was collected and documented.
RF: So the added value of working with an independent test lab that has ISO 17025 accreditation is that you can follow the results?
BA: That is correct. Inaddition to the quality of the results, you gain recognition all over the globe. Because test results, if they are not done by a quality test lab that is following the rules, could be challenged.
RF: Where do you see the European requirements heading?
BA: They are evolving because we are not done yet in Europe. The number of notified bodies and the scope of some of these will be reduced more in the next 12 months. A large number of these bodies will not be able to do what they are doing today and this is based on the internal clinical and technical competence level with specific devices. The requirements in Europe are facing big changes. In the clinical field there will be much more scrutiny on the assessment of the manufacturer’s clinical evaluation report.
The Essential requirements will be adopted in the proposed new medical device regulation. This will influence the whole market. Regulatory strategies that were fulfilling requirements in the past will not fulfill the new requirements; gap analysis and update of the technical documentation is required. In summary, this means that a large number of devices available in the European market, or other markets that rely on the CE marking, will disappear in the near future if they do not fulfil the new expected Medical Device Regulation.
This will start happening latest after 3 years of the publication of the new Medical Device Regulation (MDR). The MDR will be immediately applicable (upon publication), but in the transition phase, medical device manufacturers can still deal with the old applicable directives. At the end of three years, new applications must follow the new regulations. If manufacturers do not conform, they will not get a new approval according to the requirements of this MDR.
RF: When do you expect the pending changes to occur?
BA: We’ve been waiting for this regulation for many years. Every year we say the new medical device regulation will be coming. Based upon the latest information, the pressures we are seeing towards implementation of the new regulation and the starting activities of the triolog (the European Commission, Parliament and Council), we are expecting to see the new medical device regulation published in Q2/Q3 2016.
If you put a device on the market today, next year we will have a new regulation. You don’t have to fulfill the new regulation requirements immediately. You have three years’ time to fulfill these new requirements. After three years, new applications for device approval must fulfill the new requirements. Let’s take an example: You have a device you are developing, next year the new regulation comes in. You have a three year transition period. You can decide when you submit the device whether you want to go with the old requirements or the current regulation. You can decide because both methods are applicable.
It makes much more sense to go with the new regulation. If you don’t, when your certificate deadline is reached you will have to apply for CE Mark showing compliance with the requirements of the new regulation or remove your device from the market.
RF: How long is the current approval time?
BA: It depends on the quality of your documentation. If a medical device manufacturer submits documentation that fulfills the requirements, everything is good and there will be just one route of assessment. The product relevant reviewer are going to write a report, everything is going to be prepared for a certification process in a predictable timeline. But if the manufacturer submits questionable documentation and evidence, then this manufacturer will get a list of open questions to resolve.
The first round of your assessment is a question list. Then the manufacturer comes back with answers that are in some cases deemed not acceptable leading to a second round of assessment combined with a lot of delays. Depending upon the quality of the manufacturers’ documentation and the submitted evidence, the review and approval process can be between 30 days and two years. Those are extreme cases. 30 days is very fast. It could happen for a device that was tested according to the requirements of the directive and that has sufficient clinical data showing safety, performance and positive benefit-risk ration of the device.
A really good plan and a review that was project managed from the beginning, allow having a predictable approval process. That means the manufacturer tells us, “I’m going to submit on this date”, and we get their submission so we can schedule resources to review the file on time. However, if they say they will submit on Monday, but submit on Friday (which happens most of the time), then you may not have free resources anymore that deliver predictable services. In summary, it should be said that project coordination is an important factor that must be considered critically by both sides (Manufacturer and Notified Body).
RF: You mentioned that the CE mark has become a gateway to the rest of the world. Will you comment further on why that is happening?
BA: The CE mark is gained by fulfilling the requirements in Europe, this means the current Applicable Medical Device Directive(s) (MDD and AIMDD) for a specific device. The requirements in the US differ from those in Europe, especially with regard to clinical data requirements. The FDA differs between pre-market notification (510k) and pre-market approval (PMA) and depending on the novelty of the device either requires prospective clinical trials or accepts published clinical data as clinical evidence. In Europe currently different routes are possible to show safety and performance of a device: The clinical investigation route, the equivalence route or the combination of both. This system is currently under review but it should be mentioned that Europe was always pragmatic and reasonable in its decisions leading to opening the door for innovations 3 to 10 years before the US market. The delays in approval in the US were mainly based on the amount of required evidence during the submission.
Europe takes case by case decisions by looking on the claims of the manufacturer, the targeted medical indication and patient population, the proposed benefit, the innovation created by the device, and last but not least, the benefit risk ratio of the device when compared to the current state of the art. Based on those criteria, and in combination with the post marketing plan of the manufacturer, European Notified Bodies decide whether a device should be approved or rejected.
It should be also mentioned that there are several evidence showing that devices approved in Europe according to the current medical device requirements are not less safe or less effective than devices approved in the US 3 to 10 years later. The big question that should be raised is what the expectation of the patient is and when this patient wants to profit from the new technology. The whole issue the US has is that innovation is not innovative any more by the time it gets to the US market. This is why other markets such as some of the Asian market see the European system as a reasonable system and rely during their approval process on the CE mark of a device.
RF: And where does Health Canada fit?
BA: Having quality management certification (EN ISO 13485) for Europe supports as well the fulfillment of the Canadian Requirements. Health Canada has their own audit processes– Canadian Medical Devices Conformity Assessment System (CMDCAS) now—but this will be changing in the future. CMDCAS also uses ISO 13485. A manufacturer must submit a CMDCAS certificate with their device license applications for Class II, III and IV devices. The MDSAP Program (Medical Device Single Audit Program) will be replacing the current CMDCAS Audit Process soon. We are authorized as a third party Auditing Organization for the MDSAP Pilot Program. With MDSAP you can avoid having several audits by different authorities or different bodies with one cycle that covers US FDA, Brazil, Australia, Canada and Japan. This is really helpful. Europe is currently observing this program. We are hopeful that Europe will adopt some of the MDSAP tools in the future. This could be a way to have common understanding, regulatory convergence and effective usage of high valuable resources all over the globe.
RF: You’ve already given some great information, do you have any additional advice for cardiovascular researchers and device companies in the region?
BA: I’m not allowed to give any inside information because of compliance requirements and confidentiality agreements with our customers. Nevertheless I can tell you that a lot of manufacturers are working on new innovative cardiovascular devices. I’m seeing the Asian market grow much more than in the past. Asia is now developing and testing their own Class III medical devices such as heart valves, stents, drug eluting stents, and Occluders with the intention to gain European market access. The main market for Asian Manufacturer is the Asian, Middle East and African market. Getting a CE mark allows them to get smoother market access in different regions of the world and support quality claims.
With a CE mark, the previously mentioned countries gain more trust on the quality of the device fulfilling European requirements. With the CE Mark, manufacturers are allowed to sell the device in Europe. What is not acceptable is a manufacturer that says “I want to get a CE mark, but I will not support you with evidence for every requirement of the medical device directive because I want to sell it in Asia.” This will not be accepted. If they want to get a CE mark, they have to have a device that is fulfilling the European medical device directive requirements.
Read more interviews with Cardiovascular Pioneers.