We provide an overview of the regulations and legislations with regard to commercialisation of medical devices in the US. The product category of medical devices ranges from class I devices up to class III devices. In the US, market approval is granted by the FDA (Food and Drug Administration) upon assessment of quality, safety and effectiveness. The information provided here informs start-ups, spin-offs and biotech companies about the differences in regulatory procedures for specific classes of medical devices. By summarising the procedures for each class of medical device, we, ttopstart, aim to offer a guide through this dense regulative and legislative landscape. These insights can be used to design the optimal market introduction strategy for your medical device.

1. Device registration
and listing
Medical devices on the US market

2. FDA approval 2
Executive summary
We provide an overview of the regulations and legislations with regard to commercialisation of
medical devices in the US. The product category of medical devices ranges from class I devices
up to class III devices. In the US, market approval is granted by the FDA (Food and Drug
Administration) upon assessment of quality, safety and effectiveness.
The information provided here informs start-ups, spin-offs and biotech companies about the
differences in regulatory procedures for specific classes of medical devices. By summarising the
procedures for each class of medical device, we, ttopstart, aim to offer a guide through this
dense regulative and legislative landscape. These insights can be used to design the optimal
market introduction strategy for your medical device.
ttopstart is a science and business consulting company that serves leading researchers and innovative
companies in the fields of life sciences, medical technology and health. ttopstart is specialised in the
markets life sciences, medical technology and healthcare considering that these markets are highly
interconnected. We support clients in 19 EU countries and the US. We have noticed that companies
and researchers often experience difficulties with obtaining regulatory approval, for both EU and US.
This document provides an in-depth analysis, performed by ttopstart, of the FDA approval process in
the US and serves as a guidance document. For questions regarding the FDA approval process, please
contact FDA.

3. FDA approval 3
Contents
Medical devices in the US ................................................................................................................................ 4
(1) Classify your medical device ..................................................................................................................... 4
(2) Choose the correct premarket submission ...........................................................................................7
(3) Prepare the information for premarket submission.........................................................................11
(4) Send your premarket submission to the FDA.....................................................................................11
(5) Complete the establishment registration and device listing.........................................................11
References..........................................................................................................................................................12

4. FDA approval 4
Scope
Medical devices in the US
Modern medicine strongly depends on the use of medical devices for purposes of both care and
cure devices have become a vital part of modern healthcare and practically no diagnosis or
treatment is possible without them. Types of medical devices range from large capital hospital
fixed equipment, through high-technology implants, surgical and monitoring equipment, to
more familiar products such as wheelchairs, sticking plasters, syringes, incontinence aids, and
spectacles.
In the medical device industry, the success of a novel medical device launch can often determine
the positioning of the company over the coming years. Having a great product is essential and
a good starting point, but it is not enough to ensure it succeeds in the market. One of the most
important issues is to design a successful launch plan including which countries and/or areas
will be targeted. One of the countries of major interest in general, because of the population
and high innovation adoption, is the US. However, before one can launch their product on the
US market, developers are subjected to the so-called “FDA approval” by the governing body FDA.
This FDA approval is a regulatory permission needed before a medical device can circulate on
the US market, similar to the CE marking that must be obtained for Europe. However, there are
great differences between CE marking and FDA approval, such as the length of time of the
approval process and required level of clinical evidence. On average, the FDA approval process
takes 10 months with costs exceeding €50.000,- (based on a survey performed by ttopstart in
2014) while CE marking takes 2 years on average.
Figure 1 illustrates the FDA approval process within 5 steps: (1) classification, (2), premarket
submission selection, (3) preparation submission, (4) send submission and (5) complete
registration. Each step will be discussed extensively below1,2
.
Figure 1. FDA approval process in 5 steps.

5. FDA approval 5
(1) Classify your medical device
First, in order to select the appropriate premarket submission, you need to classify your device.
The product category of medical devices is divided in three classes based on the risks associated
with the device; class I, II and III.
Class I (47% of all devices) represent low to moderate risk devices where general controls are
sufficient to provide reasonable assurance of the safety and effectiveness of the device. Devices
are also classified as class I if the device is not purported or represented to be for a use in
supporting or sustaining human life. Also, devices are classified as class I when they do not
present a potential unreasonable risk of illness or injury. For example, dental floss and elastic
bandages are classified as Class I device.
Class II (43% of all devices) devices represent a moderate to high risk. Devices are classified as
class II when general controls are insufficient to provide reasonable assurance of the safety and
effectiveness of the device. Also, when there is sufficient information to establish special
controls to provide such assurance. For example, condoms and pregnancy tests are classified as
Class II devices.
Class III (10% of all devices) devices are generally the highest risk devices and are therefore
subject to the highest level of regulation. Devices are also classified as class III devices when both
class I and II are not applicable because insufficient information exists to determine that the
special controls would provide reasonable assurance of its safety and effectiveness. In addition,
the device is classified as class III when it is purported or represented to be for a use in supporting
or sustaining human life or for a use, which is of substantial importance in preventing
impairment of human health or presents a potential unreasonable risk of illness or injury. For
example, replacement heart valves and implantable devices are classified as Class III devices3,4
.

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How to identify the class of your device
As mentioned before, medical devices are assigned to one of three regulatory classes based on
the level of control necessary to assure the safety and effectiveness of the device. To find the
classification of your device, you need to find the regulation number that is the classification
regulation for your device. This can be accomplished by (1) searching for a part of the device in
the classification database or (2) by going to the respective device panel (medical specialty) in
Code of Federal Regulations (CFR) Title 21 parts 862-892 (21 CFR 862-892) directly. The second
can only be used if the device panel (medical specialty) to which your device belongs is known,
e.g. cardiovascular devices or Ear, Nose, and Throat devices. If you have already established the
appropriate panel you can go directly to the CFR and find the classification for your device in the
list of classified devices, or if you are not sure, you can use the keyword directory in the product
code classification database.
Figure 2 provides a simplified overview of the classification of medical devices in a flowchart. It
should be taken into account that verification of the class of the device by 21 CFR 862-892 is
preferred over this flowchart as this only presents a limited overview. For example, if the device
is a blood pressure computer that falls into the Cardiovascular device panel, 21 CFR 862-892
quickly shows that this device will be classified as class II.
Figure 2. Flowchart of class categorisation by FDA.
*General controls apply to all medical devices, unless exempted by regulations. If a device is
exempted from one of the general controls, such exemption is stated in the classification
regulation for that device.
**Special controls are regulatory requirements for class II devices.

7. FDA approval 7
(2) Choose the correct premarket submission
Once you have determined the class of your medical device, you can choose the correct
premarket submission process. The class to which the medical device is assigned determines the
type of application required for FDA clearance. As observed in table 2, each class is further
differentiated by limitations (exemptions) which then shows the type of application and
regulatory controls per class. You can determine the type of application by going to What are
the Classification Panels or go to the CFR Search page. In addition, these exemptions are listed
in the classification regulations of 21 CFR and also has been collected together in the Medical
Device Exemptions document.
Limitation Type of applicationClass
I
III
General controls and premarket approval; valid scientific
evidence to demonstrate that the device has demonstrated a
reasonable assurance of safety and effectiveness through the
submission of a PMA application
No exemption
Exemption
510k
Registration and listing
II
No exemption
Exemption
510k
Registration and listing
-
Preamendments
device
premarket approval application
510k
Regulatory controls
General controls; registration and listing, medical device
reporting, labeling and good manufacture's practice
Exempted from 510k and some from GMP. Only registration of
establishment and list generic category or classification name
General controls and special controls; performance standards,
postmarket surveillance, patient registries, special labeling
requirements, and development and dissemination of
guidelines
Exempted from 510k. Only registration of establishment and
list generic category or classification name
Table 2. Overview of classes and their respective type of application as classified by FDA.

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Types of applications
FDA has three different types of applications: registration and listing, 510k and premarket
approval application (PMA) as illustrated in Figure 3. All types will be extensively discussed
below.
Exempted class I/II devices
As illustrated in Table 1, all devices classified as exemption in both class I and II are subjected to
the limitations of exemptions, which are covered under 21 CFR (parts 862-892). The class I/II
devices that are exempt from 510k and class I exempted from good manufacturing practice
(GMP) are (or check the website of FDA):
• Preamendement devices not significantly changed or modified. The “preamendment
device" refers to devices legally marketed in the US by a firm before May 28, 1976 and:
• which have not been significantly changed or modified since then; and
• for which a regulation requiring a PMA application has not been
published by FDA.
or;
• Class I/II devices specifically exempted by regulation. The following device panels include
exempts for some devices:
• Part 862 – clinical chemistry and clinical toxicological devices
• Part 864 – haematology and pathology devices
• Part 866 – immunology and microbiology devices
• Part 868 – anaesthesiology devices
• Part 870 – cardiovascular devices
• Part 872 – dental devices
• Part 874 – ear, nose and throat devices
• Part 876 – gastroenterology –urology devices
Figure 3. Flowchart of type of application by FDA.

9. FDA approval 9
• Part 878 – general and plastic surgery devices
• Part 880 – general hospital and personal use devices
• Part 882 – neurological devices
• Part 884 – obstetrical and genealogical devices
• Part 886 – ophthalmic devices
• Part 888 – orthopaedic devices
• Part 890 – physical medicine devices
• Part 892 – radiology devices
Important note: only some devices of these device panels have an exempt for 510k. If the
respective device falls in one of the exempting device panels, it is advisable to check the
website of the FDA.
These exempted devices are exempt from the premarket notification 510k requirements subject
to the limitations on exemptions. However, these devices are not exempt from other general
controls. All medical devices must be manufactured under a quality assurance program, be
suitable for the intended use, be adequately packaged and properly labelled, and have
establishment registration and device listing forms on file with the FDA (registration and listing,
labelling and GMPs). For registration and listing, an online form must be submitted to FDA with
general questions about your business. Labelling of the medical device should be in accordance
with Title 21 of the Code of Federal Regulations which differs per type of medical device and can
be checked via the website of FDA. Next to registration and labelling, manufacturers of medical
devices must incorporate in their quality assurance (QA) program several elements that relate
to labelling in order to meet the Good Manufacturing Practice (GMP) requirements of the
Quality System regulation. The QA program must be adequate to ensure that labelling meets
the GMP device master record requirements with respect to legibility, adhesion, etc., and ensure
that labelling operations are controlled so that correct labelling is always issued and used. To
check if you meet the regulations, you can check the website of FDA.
Class I/II and exempted class III devices
Non-exempted class I and II devices are automatically subjected to the so-called “510k”
clearance. For class III, devices typically require premarket approval application (PMA). However,
unless the device is a preamendments device as explained before, this device requires a 510k for
marketing. Previously, when a device was novel and for which no predicate device existed the
device was automatically classified as class III, which required a PMA-submission. The latest
regulations provide a new mechanism, 510(k) de novo submission, which provides a mechanism
to classify novel devices with low risk as class I/II, which require a 510(k) submission. Here the
safety and effectiveness of the device have to be proven by clinical data. In general, if CFR states
that “no effective date has been established of the requirement for premarket approval” then a
class III 510(k) should be submitted. If the device consists of two components, which are
categorised in class I and class II, the medical device is categorized as a class II device.
A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed
is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21
CFR 807.92(a)(3)) that is not subject to PMA. Submitters must compare their device to one or
more similar legally marketed devices and make and support their substantial equivalency
claims. Until the submitter receives an order declaring a device SE, the submitter may not
proceed to market the device. Once the device is determined to be SE, it can be marketed in the

10. FDA approval 10
U.S. The SE determination is usually made within 90 days and is based on the information
submitted by the submitter.
Clinical data for 510k is required for class III devices and sometimes for class II devices. One can
determine if clinical data is required if the device has an important difference with the predicate
device, e.g. new indication for use or new technology. When clinical data is required, the
requirements for conducting the study are the same as those for conducting an Investigational
Device Exemption Study as outlined in 21 CFR 812.
Class III devices
An approved Premarket Approval Application (PMA) -- like an approved New Drug Application
(NDA) -- is, in effect, a private license granted to the applicant for marketing a particular medical
device. Class III without a limitation, requires a premarket approval application in order to
obtain FDA approval. This application is a scientific, regulatory documentation to FDA to
demonstrate the safety and effectiveness of the respective device, which consists of an
administrative and technical part. It is of main importance to include all listed administrative
elements in the application; otherwise the FDA will refuse to file the application. In addition,
good science and scientific writing is a key to the approval. Manufacturers should perform a
quality control audit before sending the application to the FDA. The technical section should
include both a non-clinical laboratory studies’ section and a clinical investigations’ section. The
non-clinical laboratory study for safety evaluation should include information on microbiology,
toxicology, immunology, biocompatibility, stress, wear, shelf life, and other laboratory or animal
tests. The conducted safety study must be in compliance with 21 CFR part 58 (good laboratory
practice for nonclinical laboratory studies). The clinical investigations’ section includes study
protocols, safety and effectiveness data, adverse reactions and complications, device failures
and replacements, patient information, patient complaints, tabulations of data from all
individual subjects, results of statistical analyses, and any other information from the clinical
investigations.
The review of a PMA is a four-step review process consisting off:
• Administrative and limited scientific review by FDA staff to determine completeness
(filing review);
• In-depth scientific, regulatory, and Quality System review by appropriate FDA personnel;
• Review and recommendation by the appropriate advisory committee (panel review); and
• Final deliberations, documentation, and notification of the FDA decision.
More in-depth information can be found on the website of FDA3,4
.

11. FDA approval 11
(3) Prepare the information for premarket submission
Once you have classified your medical device and selected the correct premarket submission,
you are ready to prepare the appropriate information for your premarket submission to the FDA.
The following information should be considered when preparing your premarket submission:
• You can seek device advice on both a 510(k) and PMA
• Design controls: All Class II and Class III devices must be designed in accordance with
Design Controls under the Quality System Regulation (21 CFR 820.30). See the Design
Control Guidance for guidance.
• Non-clinical testing: If needed (this depends on the device classification), nonclinical
testing must comply with the Good Laboratory Practices (GLPs) in 21 CFR 58.
• Clinical evidence: All PMAs and some 510(k)s and De Novos require clinical evidence. All
clinical studies must comply with all applicable IDE regulations and Good Clinical
Practices (GCPs)
• Labelling: The labelling for a device must be written according to labelling regulations
and included in your premarket submission.
(4) Send your premarket submission to the FDA
Once all the information has been assembled necessary for your premarket submission, you can
send your submission to the FDA and have the ability to interact with FDA staff during review.
Some important notes for this premarket submission:
• User fee: There is a user fee associated with the submission of a 510(k) or a PMA. For
510(k), the standard fee is $5,228 and $2,614 for small businesses (SBD needed; gross
receipts or sales of $30 million or less are eligible). For PMA, the standard fee is $261,388
and $65,347 for small businesses.
• eCopy: your submission must include an electronic copy (eCopy) on a compact disc (CD),
digital video disc (DVD), or a flash drive4
.
(5) Complete the establishment registration and device listing
Once the FDA has provided FDA clearance or approval, you are ready to register and list your
device facility and your devices with the FDA (also known as establishment registration). First
you need to pay the registration fee ($3,872) and obtain a Payment Identification Number (PIN)
and Payment Confirmation Number (PCN). Once obtained, you need to go to the online account
administration of FDA to register and list your device4
.

12. FDA approval 12
References
1. Basu, S. & Hassenplug, J. C. Patient access to medical devices--a comparison of U.S. and
European review processes. N. Engl. J. Med. 367, 485–8 (2012).
2. SORENSON, C. & DRUMMOND, M. Improving Medical Device Regulation: The United
States and Europe in Perspective. Milbank Q. 92, 114–150 (2014).
3. EMERGO. US FDA Registration Process for Medical Devices.
4. Health, C. for D. and R. Medical Devices. at <http://www.fda.gov/MedicalDevices/>
Contact the author
Michelle van Wijk,
MSc Consultant
Expertise Area: Reimbursement
for Medical Devices
Email: michelle@ttopstart.com