Necessity the real definition of invention – the process

Necessity is the mother of invention is a known fact to all, but what is
unknown is the real definition of invention – the process of translating an
idea to anything that creates value to a customer’s life. And such an invention
is the one of a medical device. The idea of adding value to a customer’s life with
the innovation of a medical device always goes hand in hand with regulations. Once
a medical device is innovated, the journey of this engineered product starts
from just being a design to being a finished product ready to be marketed.

There are obviously a number of steps that are involved but one very crucial
step is the approval from the regulatory body to ensure the safety of the end
user. Why does the regulatory body come into picture? What does this body do to
ensure safety? These are some general questions that come into mind when the
word ‘regulatory’ is first heard. It is so in the case of medical devices because,
they have been designed to fulfil the purpose of conducting a diagnosis or a
therapy. This being done in close contact to the human body requires high
amount of care to be taken. The role of the regulatory body in this is to
conduct the analysis of the processes and report the biocompatibility analysis
before it comes anywhere near the living tissue. This not only increases reliance
of the customer over the quality of the product but also gives the customer a
reassurance about the product. There are many regulatory bodies around the
world that administer safety of the customer.

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A few are listed below country wise in a tabular form:


Two giants that dominate the medical device market delivering value to
the current dynamic of the healthcare industry are US and Europe. The US Regulatory
Affairs for medical devices is handled by the Food and Drug Administration(FDA).

FDA is a federal organization that comes under the Department of Health and
Human Services. Its mission statement briefly states that the FDA is
responsible for the safety and efficacy of products concerning public health.

It monitors all the processes involving the product that has to be certified.

This certification allows trade and marketing of the product in the United
States. Similarly, in Europe the European notified bodies are responsible for
regulating the safety of the product. The European notified bodies approve the
product by giving it a Conformité Européenne(CE) Mark. This allows free trading
of the product across the European Economic Area(EEA). In this essay, the
differences between the US Regulatory Body and European Regulatory Bodies are
analyzed on the grounds of regulatory procedures adopted by them to ensure
public safety.

The essay highlights a systematic comparison between the US and European
regulatory bodies with two points that will corroborate the argument. The two points
are: 1) Geographic Area, Population under
Authority and Commercial Value; 2) Functioning, Value Based Judgement and Allowance
for Innovation. All the comparisons are made keeping in mind medical device
approval processes. The walk through would mean first looking at the bigger
picture and then going down to the core understanding of the role played by the
regulatory bodies in medical device approval. Later, it takes the turn to pave
the path for the dawn of a new era with the introduction of modelling and
simulation and regulatory restructuring accommodating it. And concluding, it
highlights some important insights that could help provide a medical device company
with a choice of pathway to medical device approval by regulatory authorities.


The US FDA regulates products coming to market in 50 states of the
United States, the US Virgin Islands and Puerto Rico. It has 223 field offices
and 13 laboratories all over the US. The Medical Device Sectoral Overview –
Galway City and County Economic and Industrial Baseline Study states that there
are 7000 medical companies in the US and the medical device sector has a growth
rate of 6.1% as of 2015. Reigning the global medical device market charts with
an excellent 38% of a share, US has a total annual sale of $110 – 116 billion
and has a value of $125.4 billion. The American medical device market
employees, 400,000 Americans and 2 million individuals indirectly.  On the other hand, the EMA has Competent Authorities
that takes care of the safety of the user in every member state. These
Authorities are the closest to a public health organization but are actually
set up to award the CE Mark, which allows easy trade of the medical product
across EU.

Following are the Competent Authorities:

The table mentions 30 countries that have their own Competent Authorities
that function differently in every country but have the same goal. According to
the report presented by MedTech Europe in 2012, there were more than 25000
medical devices companies of which 95% of them were Small and Medium sized and 575,000
employees were employed to work in the medical sector. 10.4% of GDP in Europe
is dedicated to healthcare and 1% of that is invested in medical technologies.

Being the second most demanding market for medical devices, with a €100 billion
revenue accounting to 31% of the market share.

Comparing the size and investment in medical healthcare, 2 differences that
take prominence are Centralization and Funding for approval process. The US FDA
has a central registration process with only one body operating the
regulations. European regulatory system on the other hand has many different
registration requirements for approval in different member states of EU. In US,
the funding is divided into a percentage of 80-20, with the greater part being
paid by the public authority and rest by the medical device company. In Europe,
the share of division varies with the available resources for testing at the
notified bodies. Notified Bodies look at this as a competitive opportunity to
get the maximum business. Although it is argued that FDA approval costs are
more than CE approval but the fact that the costs are fixed cannot be denied.


Further, evaluating the differences between the US and
European regulatory bodies comes down to the core focus on the approval
processes adapted by both of them. The US FDA reflects the functioning that has
been given a mandate to administer safety and efficacy of all Medical Devices
issued to be marketed in the American market. The FDA bases all its regulations
on the Title 21 Code of Federal Regulations(CFR). The first chapter of the code
defines laws related to Food, Drugs and Cosmetics. The 600 and 800 series are
of utmost importance with respect to medical devices.


On the basis of the estimated risk and demonstration
of safety and efficacy, the FDA puts medical devices into 3 different classes:
Class I, Class II and Class III. Based on the class in which the device is
placed, the tests and evaluations are decided. Class I is the low risk class,
example band aid which has to undergo simple tests which may or may not require
pre-market notification, Class II is a moderate risk class, example medical
imaging devices, which have to follow a more detailed set of requirements which
certainly requires a Premarket Notification and last but not the least the
Class III devices example cardiovascular valves that have the high-risk
classification have to pass the most stringent requirements like clinical trial
to demonstrate safety and efficacy which is often done via Pre-market Approval.

 The premarket notification involves in
finding a device that has been approved and marketed called the ‘Predicate’. Every
exception to the definition of Predicate is documented and conducted tests on. De
Novo or Humanitarian Device Exemption(HDE) are by default placed in the Class
III category. The use of the newest technology with no predicate in accordance
with 510(k) is placed under De Novo and if the occurrence of disease that is
intended to be treated using a medical device is extremely low (<4000 patients) then it is placed in HDE which may be approved on a 'probable' benefit basis.4 All the approved devices are stored in a publicly available database. The medical device company is obligated to report all the adverse events related to approved devices and document it in the database.


The allowance of free commercial trade all over EEA led to the
introduction of a special approval tag called the CE Mark. The 2 most important
bodies that play a crucial role in the approval process to administer safety
are: Notified Bodies and Competent Authorities. Every member state has its own
Competent Authority like Medicines and Healthcare Products Regulatory
Agency(MHRA) in United Kingdom, Federal Institute for Drugs and Medical Devices
in Germany etc. The medical devices under this jurisdiction have to undergo a
rule classification on the basis of ‘intended use’. The rule classification
system follows a hierarchical questioning approach leading to one of the 4
classes: Class I, Class II a, Class II b and Class III on the basis of
increasing risk. Some of the low risk devices are directly handled by Competent
Authorities. However, they have Notified Bodies under them which conduct
complex analyses and tests for high risk devices. The Notified Body has the
authority to assess the medical device company through audits.

All the devices have to go through the pyramid of
requirements and also have to follow conformity assessment procedure:


After careful evaluation and consideration with respect to all
documentation like Quality Management System, Design Dossier and Risk
Assessment the CE mark may or may not be provided with a full conformity report
of the same. All the devices approved with a CE Mark and adverse events related
to post market surveillance of the approved device are documented in a database
called European Databank on Medical Devices (EUDAMED) by the Competent
Authorities but are not available to the general public unlike the US FDA.4


Hereby assessing the functioning of the two regulatory bodies some
significant differences come forward: Driving Force, Data Requirements,
Availability of Information to Public and Access. The driving force behind both
the regulatory bodies is different. The US FDA is a federal public health
organization and is given a mandate to administer not only safety but also
efficacy of a medical device. Efficacy refers to the economic viability of a
device over any alternative similar devices. Whereas EMA set up the CE Mark
with the understanding of easing out commercial trade in the EU and has the responsibility
of the safety of the user and environmental health associated to a device. The Notified
Bodies designated by the Competent Authorities are non-governmental
organizations not mandated to work as public health organizations. It is the
primary responsibility of the Competent authority to administer safety for
public health. But as mentioned above every country has its own rules and
regulations for each Competent Authority. Examples of this difference are: the
approval process of an atrial defibrillator which was approved in Europe on the
basis of the data presented whereas in the US it was subject to stringent
clinical trial that led to a rejection ultimately due to a safety concern that
affected the quality of life of the patient.4 There was another product that was approved for the EU
market from 2007- 2011 but was recalled after FDA study showed a higher
complication rate than with standard care. The PMA of the approval process has
different data requirements for US FDA and EMA. All the other processes are
almost similar to each other except for this. Since the FDA checks the efficacy
of the product, it looks for a large and randomized cohort that can demonstrate
it.4 The best case that exemplifies this is the one
involving the approval process of a type of coronary artery intervention was
approved by testing it on a small group of 22 subjects6 whereas in the FDA 800 different subjects selected
randomly were tested7 to approve the device and ensure efficacy of the
device. The transparency that is maintained in the public eye. The US FDA
declares the approved medical device documentation and adverse events relating
to it publicly available. This also complies to the 510(k) to do so to find the
appropriate predicate for any future medical device. However, European system does
not make any propriety information publicly available but the information is
still stored in a database as mentioned earlier. Innovation and regulation are
two sides of the coin and the access to innovation for betterment is the first
responsibility of the regulatory body. Many reports say that the approval
process is in case of high risk devices is usually takes longer in FDA than
Europe. It clearly depends on the requirement of PMA by the individual bodies. The
best examples of this is the approval of trans catheter aortic-valve implantation
(TAVI). It received a CE Mark in 2007 and an FDA approval in 2011.


The advent of technology and an emerging medical device market, has led
to emanating a new technique for supporting the diagnosis of the device –
Modelling and Simulation. This technique was first used by engineers to know
the mathematical, physical and logical representation of a real-world problem
for decision making purposes. The accuracy and efficiency of modelling the same
situation as in-vivo meant that this could greatly impact the pre-clinical
representation study to get better predictive results of the medical device. It
was not so long ago that the US Congress and European Parliament encouraged FDA
and EMA respectively. Both the regulatory bodies have actively encouraged the
use modelling and simulation in in-silico clinical trials. But the use of this
technology indicated the regulatory framework behind it to make it perfectly
reliable for the customer to use. Since the FDA had already paved the way to
welcome this technology by approving UV-Padua Simulator in 2012 which involved
patient specific modelling, it became the first one to introduce modelling and
simulation in its regulatory documentation. In 2016, an official documentation
was issued titled “Reporting of Computational Modelling Studies in Medical
Device Submissions” which clearly defined what was expected out of a submission
that has modelling studies supporting it. Following that the European Medicines
Agency and European Commission included the using modelling and simulation as
an amendment in its directive 93/42/EEC annexes. The precursor to this
technology was the emergence of Software as a Medical Device(SaMD). An
excellent example to this is the approval process of HeartFlow FFRCT
in Europe and US.


Appreciating the facts and figures that support the argument made in
this essay, it reaches to a conclusion that the US and European Regulatory
Agencies are the most efficient regulatory bodies. The breast implant incident
that struck the whole world and with the introduction of many new technology it
was an opportune time to compare the two bodies. FDA Approval is time taking,
costly and gives comparatively less importance to innovation but guarantee the
best possible care to citizens and is consistent all over US. Whereas, CE
approval is comparatively easy going on the manufacturer but subject to threat
of adverse events. Ultimately, there can never be a situation that the medical
companies get the best of both worlds but there is no harm in considering and
diving into the pool of uncertainty which ultimately gives a great opportunity
of business and also safeguards customers.