Karim Mouneimne (L) and Frederic Mouret (R)
Optimizing Preclinical Testing During Cardiovascular Device Development
Frederic Mouret and Karim Mouneimne discuss cardiovascular device V&V challenges for cardiovascular device development. This Cardiovascular Device Pioneer Interview is Part 3 of 3 posts and covers design verification and validation (V&V) and cardiovascular device V&V challenges.
Frederic Mouret is a seasoned medical device entrepreneur with 20 years of experience. He is currently the president and the CEO of Protomed SA in France, a medical device development group specialized in the development of minimally invasive and interventional devices and the CEO of Bypass Solution.
Karim Mouneimne What are the biggest cardiovascular device V&V challenges? What recommendations do you have?
Frederic Mouret In the V&V phase, the major challenge is to have a plan. To have a plan in terms of time, and in terms of cost. If you have a plan which is well prepared, which is anticipated and well evaluated, you can do a V&V phase quite easily. It’s going to be tough as everything else. But having a very well-prepared plan is very important.
I see too many people focusing on the development of a device. They spend all their money in the development, and they arrive to the verification and validation phase, and they realize that they need to wait 6 months for a fatigue study, or 1 year to have a shelf-life study. It’s very important that everything is planned from the beginning and the project is well dimensioned in terms of time and cost. Tests are going to cost a lot, plenty of outsourced resources are needed for this.
You also need plenty of samples. You can’t imagine how many samples are burnt during the verification and the validation phase. You need to prove that your manufacturing is producible enough. You need enough samples to have valid results on your verification test. This is where I see the major challenge.
Do a plan, work on your plan, work with companies that are used to doing this. Karim, you know more than I do, ViVitro is really good at doing all this mechanical testing on cardiovascular devices, and when customers come to you, you know how to lead them to best conduct V&V and address cardiovascular device V&V challenges. I think it’s very important that entrepreneurs rely on outsourced suppliers for testing in order to have a really good plan.
Karim Mouneimne Indeed, we see a lot of people come to us, very surprised by the number of samples they have to produce to be able to go through the different phases. And very surprised that sometimes it is not easy to jump into the validation phase. You have an intermediate feasibility stage and that’s surprising. When you say “plan”, I assume you mean making sure they understand the details of each step, making sure they understand the cost and the length and delays. A very top-level plan is not good enough. Is that what I’m hearing?
Frederic Mouret You need to go into details. It’s very important because you will have plenty of surprises. And you need to do some feasibility studies, definitely. It’s not because you are working with a supplier who is doing the test every day and uses your device as is. You sometimes have to adapt the test bench or adapt the model and potentially validate even the method. So, it’s very time consuming.
Another point which is really important, is to work on the preclinical trials. We are going to do some animal studies, but we are not developing devices for animals. So, it’s very important when using and preparing the protocol of your pre-clinical trials to make sure that your device is, as much as possible, used in the best situation possible. That it’s not going to create any issues on the model that will kill your preclinical trials. It’s very important to work with professionals and companies who will really help you develop the project.
Karim Mouneimne Choose people that have a lot of experience and visibility on those processes. In the critical preclinical phase, I’ve always perceived animal models to be a challenge. In your eyes, what would be the most challenging part of the preclinical phase? We’re talking about large animal studies, right? What would be the most challenging phase?
Frederic Mouret I think one of the challenges is to choose the right model. We have the capacity to choose between pigs and bovines. You can have very different results depending on the model you choose. You have an impact on the cardiovascular system, the cardiovascular anatomy, the size of animal and the size of the anatomy and the vessels. It’s very important to choose the right model for the study.
Be aware that at some point you will also need to adapt your clinical protocol to be able to perform it in a good situation. The good thing is that there are more and more GLP testing laboratories. When these guys take on the project, they’re going to help you build a protocol and make the study as successful as possible.
Karim Mouneimne Preclinical animal studies are a huge part of medical device development. They are required by the FDA, by notified bodies, and by the CE Mark Medical Device Regulation. You can’t escape them. It’s mandatory, right? From an investment and logistics point of view, the cost is very high, and extremely high risky. In 10-15 years, do you think in-vitro, ex-vivo and in-silico, computer models, may replace animal studies? What is your perspective on the future of animal studies? If we had tools to basically replace that (animal studies) do you think it’s feasible? Can we replace that (animal studies) at some point?
Frederic Mouret I think it’s feasible, but I have some issues seeing when it will be feasible. When you are looking at biocompatibility studies, we are just at the beginning of seeing in-silico testing. We have done a lot of things in animals and now we are moving to in-vitro instead of in-vivo for the biocompatibility. Probably in-silico will come soon. It will take time.
For instance, when you are modeling a stent in Finite Element Analysis (FEA), you cannot consider all the parameters of the project. Maybe we will be in position to do this in the future. I hope so, but we are still a very long way even if the technology is more and more developed. If the technology is going very fast (and probably artificial intelligence or whatever will help to do this), then you need to convince the experts. You need to convince the FDA, the notified bodies and you also need to change the standards.
There are plenty of standards, written in black and white, where you need to do 6-month studies on animals. When it comes to changing a standard, just to change the standard it’s going to take three years or four years. So, before we are able to change the standards, we need to make sure that we have a full scientific study based on the device, which will say “OK, now we can do the experiments with in-vitro and or in-silico testing”, but it’s going to take years and years. Where I see it will also take more years, is because more and more we are focusing on the biological aspects of the devices.
When we started to develop a stent or cardiac valve, at the beginning, it was purely mechanics. But now we have new materials. We can put cells on the materials, the devices are also more complex. We are in a situation where technology to validate the device could be performed without in-vivo. But as a device is also more complicated with more interaction with biology and new materials, I have the feeling this will shift all the projects. So maybe we can expect to see something in the future, but not today.
Karim Mouneimne I understand there’s a huge challenge. Large animal testing is entrenched in the medical device industry from a standard philosophy. To change and shake this up, it will take a lot of energy. I don’t think it’s going to be a leap forward. And it’s not like you are going to jump and propose that. But maybe starting with the me-too devices, with things that are a little bit more traditional, maybe there’s a way to do that. You’re right, medical devices are becoming more and more complex. You have live tissue; cell biology makes the whole device even more challenging to test and develop. I completely agree that it’s going to be a long-term process.
Before we wrap this up, Frederic, what recommendation can you give to a medical device entrepreneur to optimize the funds that they have just received? You just got $3 million, for bypass solution. Now, what would be your recommendation to optimize the those funds?
Frederic Mouret I think it’s very important that people stay focused. It’s not because you have raised a large amount of money that today it’s going to be easier to develop the device. It’s really to stay focused, try to stay on the plan that you have developed to be able to raise this money. And be prepared to have hurdles every kilometer on your path.
It’s very important to keep an open mind on anything that could happen on the project and be able to say, “OK: we have this issue. How can w? find another way to solve this issue? Or is it really an issue? Because sometimes you have the feeling that it is an issue, but sometimes it’s not really.” It’s just a question of not thinking the project is in a good way. I would say, “stay focused on what you have and then stay on plan as long as you can”.
Karim Mouneimne Great advice, I agree. Sometimes you are solving non-issues. You’re spending a lot of resources on solving something that is actually not even an issue. That is a very interesting advice.
Thank you very much for your recommendations. I wish you good luck with the $3 million funding. The adventure continues with you. I’m very proud of seeing Protomed growing and all these activities. You are very seasoned professionals and if, there’s somebody in the medical device industry who can bring a lot of experience, it is definitely your team. Thank you very much Frederic, I really appreciate your time.
Read Part One of the Frederic Mouret interview on Bypass Solution and the End-to-side anastomosis device.
Read Part Two of the Frederic Mouret interview on how the Protomed Model Accelerates Start-Up Success.
Read about other Cardiovascular Pioneers here.
Protomed Labs SASU was a full subsidiary of the Protomed SA, before being acquired by ViVitro Labs in July 2019. Karim Mouneimne is currently on the board of Protomed SA.