Stanford Webinar: Regulation & Health-Eco Value Assess. – Two Critical Gauges for MedTech Innovation



Now I'd like to introduce Jan Pietzsch,
who is today's featured speaker. Dr. Pietzsch's professional and academic work focuses on early
stage technology assessment. And strategic decision support for
investors, manufacturers and research institutions. A primary emphasis is on evaluating the
value proposition of new technologies, and providing quantitative inputs into the
selection of promising technology concepts and their targeted development. These includes model based
assessment of the clinical and health economic benefit from
new diagnostics and therapies. He received his academic training at
the University of Karlsruhe in Germany. And also here at Stanford University
where he completed his PhD. Dr. Pietzsch is co-founder,
president, and CEO of WingTech Inc. That's the technology consulting
firm focused on health economic and value assessment. Previously, he'd been a research
fellow with the US FDA's Office of Device Evaluation. Currently, he holds an appointment
as Adjunct Professor of Management Science and
Engineering at Stanford, where he also serves as a director at
the Stanford Bio Center for Biodesign. The center is located here on campus
next to the medical school and in the center of Silicon Valley,
which seems fitting. And it's a leading program in
medical technology innovation. It's vision is for a world where health technology innovators
from around the globe have immersive, collaborative, cutting edge training
that they require to thrive. And on that note,
I'm going to hand over to Jan. >> Thank you very much Marsha. Good morning everyone, it's a pleasure
to see many of you registered here. And it's also nice to see the interest in
medical technology because it's really, I think, one of the fields where you
can combine different interest and area competencies and expertise and
really do something very meaningful by bringing technologies to patients
that really improve outcomes and that also help to manage care, and
provide services in an appropriate manner. Which is increasingly, as we see, important in healthcare
systems around the globe. We have two topics today that
I'd like to discuss with you. One is regulation of medical devices and
the second is economic value assessment. They are really critical for
the successful bench to bedside innovation process of medical technology and
so we'd like to highlight those. In this webinar there is also a class we
will mention later that I'm teaching in the spring time for those of you
interested in taking the course online. To set the stage let's look at
a couple of medical technologies. Starting from top left here, you see
a trans-catheter aortic heat valve, or which is a new way to place and
artificial heart valve. It replaces the surgical
open chest approach and is one of the key cardiovascular
innovations of the last couple of years. It really facilitated treatment of
patients that were previously not candidates for surgery and
needed to be medically managed only. And also it's a candidate who
are a technology that replaces over time surgeries. So very high patient value device and
we get back to that later in a case study. You see on the right, next to it,
deep brain simulation. Which is also an exciting neural
simulation technology that is used for treatment of epilepsy, for example. For treatment of depression. But also for
treatment of Parkinson's Disease. So a big patient impact and also,
one of the medical devices. That they contribute to reduction and
the need for medication usage. So you see a direct link actually for medical technology also can replace
pharmaceutical treatment regimens. Next to it you see an advanced stem
therapy for cardiovascular applications. You see an imaging device for
mammography or breast cancer screening,
which also has a very important field. I mean, all of imaging and diagnostics. You see just next to it,
further below, a treatment for obstructive sleep apnea,
which is a big health concern. I mean,
obstructive sleep apnea is a condition, because it really elevates long-term
cardiovascular and stroke risk. And in patients who don't
tolerate CPAP treatment which is a mask based treatment
to treat sleep apnea. A new device has been developed that
again uses neurostimulation technology to stimulate the tongue base at night and
thereby keep the airway open. Then you see a diagnostic device for
glucose monitoring which you can see over the counter or can purchase
in any pharmacy in the United States, certainly at the large need,
or large number of users. But their continued advancements,
also with the connection to mobile health technologies that really facilitate better
management of the condition of diabetes. Then next it, to the left,
you see a new approach to actually diagnosis lung cancer and
to avoid invasive procedures. It's a genomic marker test. You see here a bronchoscopy
being performed and a brush that is used to take a sample
which is then analyzed in a lab. To determine the risk or
the likelihood that the patient actually does have
a cancerous condition or a lesion. And by using such new technology there is the opportunity to reduce
invasive surgical biopsy. And you can imagine that that's really
a risk reduction for the patent and it's a benefit also for the healthcare system in terms of
avoiding costs of complex procedures. Then a device that is a family of devices,
artificial joints, you see the hip joint here excuse
me the knee joint, roughly 700,000 total knee replacements are performed
per year in the United States alone. And again, big impact on patient quality
of life in patients with severe arthritis. But also a big market for medical
technology or orthopedic technologies. And then finally, technology that's
a high flow therapy respiratory support systems that are gradually replacing
more invasive respiratory support, mordalities, such as antiobasin
other wise mask based treatments. Again, I think all of these
technologies and there are many, many more show you the wide
variety of technologies and the wide variety of opportunities
to really improve patient care and patient outcomes. Now for all of these technologies,
if you're thinking of innovations in those spaces, right,
we need to think about demonstrating the value of these technologies to
the patients or at least developing and understanding, right, how meaningful
a technology is to patients. We also need to think about
the questions of safety and effectiveness of these technologies. And the leading question, our lead
question really is what constitutes safety of a medical technology? What does it take to demonstrate
safety and effectiveness? Next do we need to worry or
think about the target population. If there's a very narrow defined
population that could benefit from the therapy or the technology,
or is it a larger target population. Thinking of the knee replacement,
$700,000 per year number of devices. That's a very different to
some other technology areas. So we need to appreciate and
define the target population, because it also has an affect
on the safety profile and on the effectiveness profile and
we'll discuss that in a minute. And then finally,
is this technology of value, right? Should it be paid for, and if so,
What amount would be appropriate for healthcare systems. And we also need to keep in mind that
this value question really is stakeholder specific, and it's country specific. So a technology that might be
of value in the United States. Healthcare system might not be of value
in other healthcare systems like the UK, France, Spain, or Japan. And the reason is that we not only
might have some slight variations in the underlying clinical profile. But we have very different
implementations of healthcare systems and also different cost structures and
cost profiles. And so you see that all of these questions
really directly relate to the fields of regulation and
health economics that we discussed today. And a point here that we should
mention specifically here is that very different from other industries
like the automotive industry or many consumer electronics fields. Commercial success and bringing
a therapy really to the patient for commercial use means that we need
to rely on approval by regulatory authorities in the United States
the Food and Drug Administration. And we also need to obtain reasonable
positive reimbursement that actually allows us to
a business in the end. So without those third party
considerations or approval by third parties, there's no way to have a
successful translation from development or R&D to the clinical use and
the patient benefit. So that means we need to understand very
thoroughly the requirements of regulatory approval, and of reimbursement
approval and value assessment. And there's a direct link as you probably
appreciate between the requirements and the commercialization risks and
rewards of the time to market, imagine for example, a required two year followup
study as opposed to six month followup. That very much affects
your time to market and it also affects the costs of
development and clinical testing. And that leads us directly also
to the funding requirement, when you think of raising funds for
a new concept or new technology. The questions of what
aspects of regulation and reimbursement really drive heavily
the funding requirement question as well. And there's an increasing importance
globally to demonstrate value in a changing healthcare environment. So let's talk about regulation. Couple of years ago, we did a study at
Stanford Biodesign where we outlined the medical development process from the
very early stage of need identification, all the way through post market and
you see, key activities listed here. You see also decision gates along the way. And what was really striking, is that
more than half of the activities and the decisions are governed by regulatory
and reimbursement requirements. Most of them actually
regulatory requirements. Second point I'd like to make here is
that regulation not only relates to the approval of medical technologies or
the pre market review, as it's called. But also to the full life
cycle of a medical device. So all aspects of surveillance in
the field managing feedback that you received from patients and
providers about issues with the device. Manufacturing, productions,
all of those aspects are regulated and governed by regulations. And so In order to successfully manage
a business, you need to be aware of those requirements, and
implement procedures accordingly. Two important definitions that govern
FDA's work when evaluating technology, you see the legal definitions from
the Code of Federal Regulations for Safety and for Effectiveness. And let me just read them to you. There's reasonable assurance that a device
is safe when it can be determined based on valid scientific evidence
that the probable benefits to health from use of the device for
its intended uses. And conditions of use when accompanied
by adequate directions and warnings against unsafe use,
outweigh the probable risks. Again, in the definition of safety
you see this balance of benefits and risks, or that the benefits
need to outweigh the risks. You also see a couple of
important definitions. One is the question of what
constitutes valid scientific evidence. Is it a randomized control? Try it, for example,
with the highest level of evidence. Or it is sufficient,
for some technologies, to use less comprehensive data to use,
for example a single arm study, and compare the results to previously
published results from another technology. So this is a very relevant and
key question. And also is actually one of the drivers in the implementation of
the regulatory process. You may have heard about
the regulatory pendulum. That there were differences between how
to administrations actually enforced regulation. And implemented regulation as one of
the key drivers here is the question, how much evidence is needed and what is
considered to be valid or valid enough? Another definition is the intended use. You cannot get clearance for a technology. For use in any patient,
it's always for one specific or several specific indications per
user intended to do with this. And you also need to be
careful in describing and specifying what is the condition of use. Is it in an inpatient setting and an
outpatient setting, who is performing or using the device,
all of those are relevant questions for the regulatory review process. Labeling is part of that,
as well as the instructions for use. Effectiveness, looking further below, there is reasonable assurance that
a device is defective when it can be determined based upon again
valid scientific evidence. At any significant portion of the target
population the use of the device for it's intended use and conditions of use
when adequately to the warnings against unsafe use they provide
clinically significant results. Again definitions of valid
scientific evidence. Also definitions for
intended use in a given population and also the definition of clinically
significant results that means the FDA. For example, the European regulatory
requirement FDA really evaluates the benefit to the patient in terms of
outcome, in terms of effectiveness. It's not sufficient to agree that
a technology's safe enough, but it really needs to demonstrate
a clinically significant improvement. In Europe, the focus with the labeling,
for those interested and familiar with the European system Is
to evaluate safety, and performance. And performance means,
not the clinical performance, but that revise does what it's intended to do,
but there's no long term evaluation of outcomes as part
of the regulatory process. How is regulation implemented
in the United States? When Congress enacted medical
device regulation in 1976, following pharmaceutical regulation,
which was in place since the 1930s, with the Food, Drug, and Cosmetics Act. Congress determined that for medical
devices and, again, differential pharma, it does make sense to consider
the risk level of a device. Because, you can imagine,
medical devices like syringes. And you see the photo here on the right,
have a much different risk profile than a intracardiac stint or
catheter. And so the three risks, one, two,
three, increasing in risk level. And the review requirement are different. There are exempt devices that really
require only the registration of the manufacturer but no submission
of clinical or other Test data. Then there's the so-called 510(k) process. The definition actually goes back to
the Court of Federal Regulation section. It's the typical process for
Class Two devices, and it requires demonstration of substantial equivalent
to one or several predicate devices. So as long as you can show that your
technology performs similarly to an existing technology, or
uses technology components that were previously cleared
through the 510(k) process, you can demonstrate would be upper
review by FDA, you can demonstrate if you're successful that the technology's
substantially equivalent. And therefore should be cleared
to market via the 510(k) process. Then there's pre-market approval or PMA,
which is the highest regulatory process. It's very much comparable to
the new drug application process. And medical devices always
require a trial-based evaluation, typically with several
phases of clinical trials. In addition to pre-market evaluation and
clearance as I mentioned earlier, there are regulations governing
manufacturing and other aspects, quality system regulations, R&D processes
manufacturing, procurement distribution, product surveillance and
many other aspects. FDA review was actually
a paper-based review, I mean even though lot of these
papers are now electronic. But it's not that FDA evaluates a device,
takes it apart and studies its risk profile. Companies submit documentation of
tests that were performed, and you see how comprehensive these dockets
are, this is for a PMA-type device. And what FDA receives and then needs
to review within 180 days typically. And you can imagine that
that's a tall order, and a very comprehensive task involving
biostatistics, engineering, medical disciplines, and so on, and
we expert knowledge within the agency. As mentioned earlier, the implementation of the regulatory
review process has changed over time. This show is a shot comes from
the latest MDUFA report that FDA published just early this year. And it shows the pre-market approval,
again the highest risk does divides approvals, and
you'll see in green the successful or approved devices and
how that's changed over the years. And you can see, for example, with
the beginning of the Obama administration in 2008 and 2009, the approval rates for
PMAs really went down significantly. And that was the results of stricter
requirements that the new administration or the new leadership at FDA
implemented at that time. Since then it has dramatically
increased again, and FDA has been very successful actually
in further improving its operations and procedures, which is good news to
everyone involved in the industry. Now let's switch over to our second topic,
health-economic value assessment, to give you some background about
the environment that we all or anyone operating in the field
of medical devices. Now, in these two phase, you see for
the United States, again, the total federal spending is percent of
the Gross Domestic Product over the years. And you can appreciate or see here in red,
the major head programs, that's Medicare and Medicaid, primarily being the highest
spending category of government spending. Roughly 5% of the GDP and consider that this is only
the government part of health care. When you add all of the private aspects,
and commercial insurance aspects of health
care, you're currently looking at 18 or 19% of the the GDP being spent on
health care in the United States, which is roughly double what
other countries in Europe spend. And it's not only in Europe, but
especially in the US it's a concern, especially when you look at
the projected future expenses, which are driven among
other factors by changes in the age groups, for example,
of patients, demographic changes. And you can also appreciate that's
just occurred or what's proposed. If defense spending, which you see
further down, is increased by $50 billion from one year to the other at the expense
of other government spending categories, that there is even more pressure on
spending on healthcare for example. Right, and that means also,
there needs to be significant scrutiny, and funds should be spent
wisely on technologies or aspects of healthcare that really
are meaningful and contribute value. And that's the environment we live in and that we are increasingly
facing going forward. Therefore, not only in
the United States but globally, any healthcare system,
regardless of their ability to spend, and the absolute amount of
spending on health care. All health care systems face
the issue of improving or the desire to further
improve patient outcomes, while also managing costs, controlling
costs, in some cases, reducing costs. And so technology really can
contribute significantly to helping resolve these issues, right? We just need to make sure that
the technology we're bringing forward really address one or
two of these concerns. Ideally both of them, right, in outcome improvement and
overall same or reduced cost. Now when we look further at value, we need to appreciate that there
are different stakeholders involved. It's not sufficient to only look
at Medicare, for example, and show that Medicare expenses, even though
that's very important and relevant, right? If Medicare expenses are reduced with
the introduction of a new technology, it might be that it comes at increased
cost, or lower revenue margins for the hospitals, right? And so, from a hospital perspective,
from a pure financial perspective, that would mean that it's not of
value to adopt a new technology. And so keeping in mind that
the argument driver should always be an improvement in patient outcomes,
but on the financial side, we need to be aware of those ramifications, and
be aware of different stakeholders. We need to think about demonstrating
incremental improvement, compare the status quo. Which also means that
we need to identify and very carefully appreciate how
technologies are currently, or how patients treated with
existing technologies, right? And we need to identify
the incremental changes. We need to have a focus on cost and
outcome, demonstrate the long term perspective. And consider not only the episode of care,
but also the longer term implications
in terms of costs and outcomes So from a patient perspective, again,
going back to the clinical objectives of any new technology, we need to be able
to demonstrate either a reduction mortality survival improvement, or
a reduction in patient morbidity, or a improvement in patient
related quality of life. In some technologies, actually, we're able to address all of them,
but keep in mind that these are the three drivers really that
drive the value proposition to a patient. And we need to be able to demonstrate
a viable economic profile, a therapy needs to be either cost-saving
or cost-effective to be of value. And that is measured through
the cost-effectiveness ratio, on the right-hand side you see a graph
where you see at the zero point or the cross of the axis,
the existing approach and technology, how a patient might be
treated and given an indication, and we are looking at The difference in costs. There's our costs on the y axis. And the difference in outcomes or effectiveness of measured in quality
adjusted life here is to the right. And you can appreciate that
there might be technologies that lead to better patient
outcomes at higher overall costs. And up to a certain willingness to pay
threshold that is defined by individual healthcare systems, the technology might
be considered to be of good value, to be cost effective. And that means it should be adopted. There are also technologies
that hopefully in the future, more technologies that
improve patient outcomes. But also reducing overall cost
to the healthcare system, and it would be in the quadrant
on the lower right. When we think of developing technology
that leads to higher costs, and many, many, increased effectiveness that
lie above the willingness to pay threshold here, then you can appreciate that they're
not considered to be of good value, and would be very hard to actually get a
successful adoption of those technologies in the future. So the implications continued here
we need to again, appreciate all of the requirements and how agencies like
in the UK, the National Institute of Clinical Excellence,
how they evaluate technologies and we need to collect data in a prospective
way from the very early stage of development all the way through clinical
and be aware of those requirements. Let me briefly go through a case study for
TAVR, transcatheter aortic valve replacement, remember that we looked at
this technology on the very first slide. And, I'd like to briefly discuss with
you the safety effectiveness and value assessment,
based on this real world technology. Brief background about the medical
condition aortic valve disease. The aortic valve is actually
the most important. All of the heart valves are important,
but the most important valve or highest pressure valve, actually between
the left ventricle and the aorta and the main body artery vasculature. And in many patients, aortic stenosis in older ages leads
to a narrowing of this valve. In the old days and up to now, the main treatment approach was open
heart surgery, which is the on top here. Which requires a very invasive procedure,
open chest, and you can increase the. Now what that means in terms of length of
stay, in terms of quality of life impact, of the mortality impact in fact. And transcatheter aortic valve replacement
is a new technology that has been introduced over the last decade to average patients that are not candidates for
surgery because they're too sick, too ill, and wouldn't survive or
possibly survive surgery. And increasingly, this approach is
also used to replace surgeries and candidates that are at intermediate risk. And you can see on this image here on the
right-hand side how the valve is actually implanted through the catheter without
opening the chest of the patient. So now if we look through
the regulatory or the value lens again, it's starting with the question
of general evaluation of TAVR, we probably should compare this TAVR
approach against surgical treatment, in patients that are candidates for
surgery. In patients previously not candidates for
surgery, we need to compare against the existing paradigm for these
patients, which was medical management. So again it shows that we
need to carefully present and understand what the patient
population that we're looking at when evaluating the technology, and also
what the current paradigm of treatment. Because that drives our incremental
differences in terms of patient outcome, and in terms of cost. How should we evaluate the effectiveness? Well it's the long term survival that
really is the most meaningful factor here. So we need to appreciate not
only the procedural success or maybe six month follow up outcome but
ideally the remaining lifetime of the patient and how survival is
affected by this new technology. We also need to think about
events like strokes and heart attacks that might be affected
by the use of the technology. And to assess those outcomes, ideally,
we would want to see one year or two year outcomes from a trial
to be able to evaluate that. There are also factors like
six minute walk test and other approaches to evaluate
the functional ability of a patient. All of those factors in sum
really drive effectiveness and do have an impact on the quality of
the That we're measuring and Analysis. What cost elements do we need to consider
when comparing TAVR and surgical AVR? So the main stay treatment,
open chest surgery. We need to consider, for example,
the number of intensive care days that are required after one
versus the other procedure. We need to consider length of stay. And we need to consider certainly
the cost of the wealth, a transcatheter aortic heart valve
actually costs around $30,000 in the United States versus
maybe 6,000 for a surgical belt. And you can imagine how that
factors into the cost equation and the cost difference equation. So what clinical data are needed
to support cost calculations? As I mentioned earlier on
the effectiveness side, there are parameters like stroke rates,
and heart attack rates that might also be influenced by the use
of this different technology. And certainly we want to capture those
also on the cost side as the treatment of this drug has immediate cost
implications and long term implications. More data sources could be used
to support a cost assessment where we could do a micro-costing
approach during the trial. That there's also extensive literature or publication based data available that
discuss the cost of a stroke treatment or to discuss the cost of an ICU aid,
intensive care aid. But there are a number of sources we
can rely on when performing these health economic value assessments. My therapy difference is between
that groups of patients, absolutely. So again it shows that we need
to be aware of the specific target population that we're evaluating,
not only from a regulatory perspective but also from the health economic perspective. And you think of high risk patient or
extreme risk patients for example, versus intermediate risk patients,
the safety profile and the health economic profile
could look very different. And you should also appreciate that
when going back to the benefits outweighing the risks equation, right. Or the scale here that we saw earlier
that certainly the risks in patients that are at extreme risk are much different
than patients at intermediate risk. Right, so keep that in mind. If you're interested in reading more
about the health-economic evaluation of a transcatheter aortic heart valve, there's an interesting
study by Reynolds and colleagues that was published last year
and they give you the reference down here. But it shows what we just looked
at this plane of cost and effect, and the likelihood that the technology actually would be
cost-effective when considering a threshold of 50 to $150,000 per college
supply period in the United States. And the conclusion of that study was even
though technology costs more from a health care system perspective,
the improved outcomes actually lead to a very favorable
health-economic profile, willingness to pay off the society as
stated in the United States between 50 and 150,000 Means that this should be adopted,
even if it's higher cost. There are also a couple of
interesting regulatory documents. The pre-market approval PMA summary
of the Transcatheter Heart Valve device is available under
this link at the agency and you find all of the documentation
of the clinical studies and pre clinical studies that were performed,
so it's very educational. Similarly as I mentioned
the cost effectiveness article. So to briefly summarize without regulatory
approval there's no market access The key criteria for approval in the United States
are safety and effectiveness. We need to determine early on, how the product will be regulated because
that drives the regulatory requirement. We also need to appreciate detailed
requirement with regards to clinical testing and so on for
each of the FDA pathways. And FDA online resources are available
again if you want to study further. We can also learn from published
documents of prior approvals and panel meetings that are published on
the FDA website, a trove of evidence and information that really is very helpful. And as discussed and then a population
appropriate comparative predicate endpoints can be gleaned
from those publications. QSR, good laboratory practices,
and good manufacturing practices, as discussed, are additional
important elements of regulation. On the health economics side, we have
seen that health economic evaluation increasingly is a critical requirement. Any health care system that wants to make
meaningful decisions about the adoption of devices and their reimbursement
price needs to evaluate the healthcare benefits and the patient
benefits and the cost of the technology. And that means for us,
from a innovator perspective, that we need to be aware
of those requirements. We need to actually collect information
during the trial and during development, already collecting evidence that we can
use to demonstrate the value proposition. We also need to appreciate what are the
key value drivers of a new therapy, very early on in development. And we need to appreciate that it's
not only the episode of care or episode of implantation, but the long-term implications and effects
of the therapy that we need to consider. Value is defined by incremental changes
from current status quo, so we need to appreciate what are the current therapies,
what are the outcomes, and the cost. And, again, we have differences
between individual countries. Useful resources for
health economics are HTAs or health technology assessment reports that
are published and publicly available as well as cost effectiveness
studies in the published literature. So, with that, I'd like to briefly
say a few sentences about 256, which studying this year actually
has lifted bioengineering course, bio e256 tech assessment and
regulation of medical devices. It's a course that is given Fridays,
1:30 to 3:20, nine sessions total available through SCDB Lectures include
guest speakers from industry and the FDA. And also, a hands on team based
class project investigating a real world medical technology report
from the regulatory perspective but also on the health-economic
value perspective. And you can find details on
the website which is given here. Thank you very much. >> Thank you very much that
was a great presentation. And now, I'd like to hand back over to so he can answer some of the questions
that you've been sending through. >> Thank you Marsha. Thank you for all of your questions. We did receive a couple of
them that are listed here. And let me just go into them step by step. One of you asked about the designed
thinking process or concepts and how they have been used and
applied in the medical technology field. And some of you that are not familiar
with designed thinking, it's a process that was defined at Stanford and
at IDO Evaluating or using concepts of use identification, by observation and
those contents have been implemented, mainly in the process,
taught at the center, that mentioned earlier Her fellowship
is offered that emphasizes heavily the early phases of the process
of medical technology innovation, where we try to have the fellows spend
time in the actual clinical studying. And observe processes, to identify needs,
and then in a very careful manner and process narrow the needs down into
the most important needs that then lead to the next step which is actually
innovation or inventing technologies and then figuring concepts down to one
final product or product idea. So, the design thinking process is really, we think, very aptical with medical
technology and has been used for 50 years in the prior designed program
very efficiently, and effectively. But, how do you prove, next question, how do you prove value on something
like preventative medicine? A very good question, and indeed there are
important programs that are supported by technology also where you try to avoid or
improve the long-term patients outcome for things, for example,
with weight management and obesity. You can think of cardiac risk factors. If you manage them effectively, you can
influence the long-term outcome and the benefit of the technology. Are evaluated prospectively and
sometimes in modern day assessment. So, you try to appreciate how behavior and
certain parameters like blood pressure or weight are affected
with the use of such program. And then, you can project
the likely long term impact and evaluate whether it would be meaningful,
both in terms of outcome, but also in terms of cost, so
a very good question and there are many technologies actually
that focus on the parantative field. There's one question about transcarotid
back replacement here I mentioned the roughly $30,000 cost that is published
in publications in the United States. And the question is what is the price? There are some variations. And again, just going back public domain
information in European countries. According to publications It's
in the range of 20,000 Euros. Again, variation within those countries
but yes, there are global differences. But we need to also keep in mind
that healthcare in general and healthcare systems costs are very
different in these other markets. And certainly, pricing of technologies impacts the value
proposition of the technology as well. These are all very intertwined aspects. And we just look at
the next question here, how will the changes in development of
medical device regulation in Europe and in Asia affect the development
of innovative medical devices? For a long time, Europe was seen, from a regulatory perspective, more
innovation, and that still is the case. But there are some changes
in regulation on the way, currently need to be approved
by the European Parliament, to be implemented, but
especially for high risk devices. The requirements are now suppose to
be a little bit more stringent and also to the PMA evaluation
in the United States. In Asia there are changes,
in Japan it was significant. There were significant issues
with a review process in that it took a very long time. And you can imagine that very long review
time means also delayed patient exits. And the Japanese had their authorities
that worked hard in improving a more rapid review while maintaining
high levels of safety and effectiveness. But certainly those factors of global
regulatory systems also influence companies' strategic decision-making
about initial markets to access and gain clinical experiences with,
and commercialize. And I think there's one more question
here about doctor regulations can be, would I talk a little bit more
about doctor regulations. Certainly, when you look at
the technologies we've evaluated, or looked at, early on,
deep brain stimulation, heavily driven by doctor right when
you think of an ECG machine, or even this mammography device that we
looked at, software plays a big role. And FDA has guidelines for software
regulation, and for software testing, and for failure modes and effect analysis. So they are a key cornerstone of the
review process, certainly not an easy one. And I think their continued
efforts to study better or develop better approaches to evaluate software and
determine how much radiation and testing do you need to do of doctor to
make sure that it's reliable enough. Something that is not only limited
to the health care industry, but also to other industries
like automotive and aerospace where you face the same
issues of software reliability. >> I'll jump in with one that came in a
little bit later, but start-up companies, is it critical to consult with the FDA
ahead of time to prepare for approval? If so, how to establish the connections? Perhaps with your you might
have some experience with that. >> So it is always a good idea to
first use the published resources. And I mentioned the FDA website
with a lot of useful information. So, once you've done with a company
the homework and evaluated as good as you can the resources, I think it's always
a good idea to reach out to the agency and have an early dialogue. But you increase
the likelihood of success for outcome if you have done your
homework internally beforehand. It's also a center at the FDA that's
called DICE, division for industry and consumer education, which has a hotline
and provides free advice to companies. And so I think the first step,
in terms of FDA interaction, aside from the typical regulatory review
branch, context and division context is to make use of that free advice
through the center, again it's D-I-C-E at the agency and they provide
webinars and also a telephone hotline. That might be a good first segue,
especially for small companies who experience
this process for the first time. >> Great, well thank you again for
the talk, Jan, and also being able to give really
helpful details on today's questions. Thank you everyone who sent them in. I'm afraid we didn't have a chance to get
through all of them because of the time. But hopefully you found a lot that's
useful to take away from that. And enjoy the rest of your day.

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