Cell-free DNA Prenatal Testing: Differences between the U.S. and Europe, and testing for Microdeletions

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Phillips Kuhl:
Hello. My name is Phillips Kuhl and I'm president of Cambridge Healthtech Institute. For the past several years I've also worked to organize CHI's advances in prenatal molecular diagnostics conference with the third annual U. S. meeting coming up shortly in Boston on November 16th through the 18th. I've also organized a similar conference that takes places in Lisbon each spring covering advances in prenatal molecular diagnostics in Europe. One of the areas where the most significant recent changes in prenatal screening has taken place is the explosive growth in testing based on cell-free DNA from maternal blood. This approach has been very appealing, both because it is highly accurate and because it can be done non-invasively without any risk to the fetus of miscarriage.

Today, I'll be speaking with two representatives of Premaitha Health, which has been developing a kit to facilitate in-house sequencing of cell-free DNA from maternal blood samples. My first guest is Peter Collins who is Chief Commercial Officer for Premaitha Health. Hello Peter.

Peter Collins:
Hi Phillips.

Phillips Kuhl:
Let's get started by asking the first question. How does the prenatal testing market differ between the US and Europe?

Peter Collins:
There are a number of market differences but I think we should look to focus on, bearing in mind that Premaitha's developed a product, is to look at this from a product perspective. There are a number of very important factors that need to be taken into account to developing any IVD products for a particular market. (Delete: And) Here, when we're discussing the difference between Europe and the US, you obviously have to consider the intellectual property freedom to operate situation, you need to consider the regulatory requirements, you need to look at market access and reimbursement and particularly for an NIPT cell-free DNA test for pregnant moms is the pre-existing prenatal screening infrastructure that may or may not exist in the different countries of Europe and how that figures out in the US.

The IP front is obviously quite important, we don't need to go into big details but there are very major differences between how patenting and intellectual property is dealt with in the US and Europe as we've seen in the US in recent times. The Prometheus Mayo ruling from the Supreme Court has had a significant impact on the IP landscape and some of the claims in this space.

On the regulatory side, if you're going to develop a product here as opposed to a laboratory developed test, there's a pretty rigorous process for what in this case would be a class three device. It's anywhere between three and five years work to fully develop a device of this nature. The category would be a PMA which is the entire system, all instruments, all reagents, all software including the report get looked at. Europe is similar. In this case, it's a filing, run through a notified body. It's not self-declaration and it probably sits somewhere between a 510K and a PMA, for those who are familiar with those terms and at Premaitha, we have CIVD on a full workflow from DNA extraction through to the result. On the market access front, then that links into any existing prenatal screening available. The previous gold standard for trying to provide pregnant women with information about their likelihood of risk of their carrying a fetus with some chromosomal abnormalities was based around biochemistry screening and nucal-translucency from the first ultrasound.

In the US, there was some guidelines there but there wasn't really the same kind of preexisting prenatal screening available for the entire population that we see here in Europe. Screening tests are actually, in most countries in the European union, covered by a national screening body where it's considered to be a fundamental human right and a level playing field for population screening, not governed by the ability to pay, needs to be understood, debated, opined on and then put into place by government. Those kind of restrictions don't exist in the US in quite the same way and as you know you can, via the laboratory developed test approach, you can gain reimbursement codes, you can then work with the insurance companies to ensure there is coverage, via insurance companies for a test that can be demonstrated to offer clinical and hopefully economic value to the healthcare system.

The process here in Europe is really quite different to that so there's currently no governmental or single payer reimbursement of NIPT. It's pretty much entirely a private pay market. That's why we've seen an initial rapid uptake but now a kind of plateauing in Europe while we wait for the existing prenatal screening approaches to incorporate an NIPT alongside the existing infrastructure. We haven't had quite the same continued exponential growth that we've seen in the United States.

Phillips Kuhl:
As a quick follow-up question, could you talk about some of the implications for end users between doing in-house sample testing versus sending those samples out to service for prenatal testing? What do you see as some of the pros and cons of these two different approaches?

Peter Collins:
The central testing lab model, well established in the US, is not established in the same way here in Europe. Europe's much more decentralized. I guess one of the obvious advantages of a local implement product solution in your own lab is turnaround time. You've also got the advantages of being able to provide local language support and within that particular hospital group or that particular hospital, you can coordinate other metrics related to the pregnant mom. You also have the benefit that if you did need a redraw, it's much easier to get someone in, take the blood and run the test again. There is, of course, the situation now where many governments, not only in Europe but all around the world, are no longer quite so happy to ship samples across borders. When you couple that with the fact you can have regional centers that can be hubs to disseminate the same tests, you do have some more flexibility and I guess operating your own lab or labs in country does give you control of your own costs.

On the negative side of that, obviously, any lab wanting to setup with this, there's a significant investment with capital equipment, which if you're sending out you don't have to deal with. There's always the issues of lab space and of course staff to run the service. Another question is every healthcare dollar, wherever you are, or Euro, is competed for, and so there may be other competing projects that require infrastructure that the healthcare system might choose to invest some of that money in a different project and send out and takeaway some of the headaches that go around managing and providing the service.

I think obviously, on the service model itself, as we just described, no capital equipment investment, space, etc. are important pros but you do then have to deal with some fairly complicated logistics especially if you're going to be dealing on a kind of transcontinental basis. The initial labs in Europe relies on the west coast of the US or in China and that still remains, a lot of samples in Europe, in fact, who knows maybe the majority currently tested, are still sent in a plane transcontinentally. Inevitably, that does mean much longer turn-around time and of course there will be additional costs involved for the shipping and the infrastructure, etc that make it over the long term a less compelling option. I think wherever the people can provide the local service the way Europe's structured, then that will have some benefits for the local community.

Phillips Kuhl:
Thank you Peter. One critique of testing based on cell-free DNA is that all the original versions of this type of test focused on a limited range of results, screening at the full chromosome level for the most common aneuploidies, specifically a third copy of chromosome 21 which is responsible for Downs, chromosome 18 or chromosome 13. There has been interest in the potential for extended cell-free DNA testing to cover sub chromosomal genetic aberrations such as micro-deletions. For that topic I'd like to turn to Dr. Pepper Denman who is Chief Medical officer for Premaitha, welcome Pepper.

Pepper Denman:
Great question. The existing challenges are considerable. As it stands now, some battery technologies just cannot be shipped on an aircraft for example. Major restrictions are in place. That's because of the fire issues, fire and other safety issues. We do a lot of forecasting with ESSPI. We look at what some of the future challenges will be. Some of these challenges will be caused by regulations, rules and laws.

Right now the focus has to be on making safer batteries. We also need to focus on how we ship these batteries, how we manage the process. What processes do we have in place to mitigate potential safety issues?

As we move forward, more focus has to be placed by everybody in the battery life cycle. That includes manufacturing, R&D and testing, logistics and the Authorities Having Jurisdiction on better containment systems for shipping and storage.

We look at the process of shipping and storage as a closed-loop event. The same systems that the batteries are shipped in should be the systems that the batteries are stored in. There's no reason to take them in and out. They can be used when they're needed. When they go bad, for example, they can be put in these systems and the systems are fire-protected and contained.

We look at the wider issue of shipping and storing batteries as one. We try to make sure that we design systems that can do both. Again, the focus right now is on developing systems, what we call passive fire suppression technology: fire suppression technology that will prevent the battery fire from spreading out of its container and to the rest of the plane. In this example, the aircraft. We have to look at a closed-loop process that involves shipping and storage.

Phillips Kuhl:
Phillips and CHI, thank you so much for this opportunity. As Phillips said, we're going to focus on the inclusion or exclusion of micro-deletions in prenatal screening for this podcast. The other aspects of prenatal screening are very well covered elsewhere. Many people want to know should they test for micro-deletions. We at Premaitha believe that this field is still early, the learned bodies have all respectfully opined and said that they do not feel that it is the right time to be doing broad screening for micro-deletions.

Let me get give you a few examples of why we at Premaitha feel this is the correct approach. The detection rate of microdeletions, if we use 22Q 11.2 as an example, is determined by many factors but of course micro-deletions as it implies are very small elements; size, fetal fractions, sequence count, and regional variance all impact the ability to be accurate in your testing. It's hard to know exactly what the right number is but it is probably optimistic to believe we would get even up to 80 percent detection rate for the average micro-deletion. It's also felt from Yaron's work that the false positive rate is going to be .75 percent. The prevalence is only 1 in 4,000. If we run those numbers in 100,000 pregnancies we will detect 80 percent of 25 which is 20, and we'll also end up with 750 false positives. In effect, sending 750 women, should all of the rest of their testing be normal, for an amnio which didn't need one.

When we think about it, we may end up negating many of the benefits of NIPT screening for 13, 18 and 21 by searching for conditions with low incidence, difficult to detect and driving our false positives up. The other issue in some of these micro-deletions is we're not sure what the genetic finding means for the phenotype. Therefore, based on the complexity of the micro-deletion screening and how to help mothers understand that, we believe at the moment, we should not be generally testing for micro-deletions. Premaitha will continue to follow this area of pre-natal screening very closely, working with our key opinion leaders and learning societies and support the obstetrics and prenatal community as we make pregnancy and child birth safer.

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