The 510(k): Its Purpose, Compilation, and Submission

[
Device Validation Forum.
John E. Lincoln, Coordinator
The 510(k): Its Purpose,
Compilation, and Submission
John E. Lincoln
“Device Validation Forum” discusses regulatory
requirements, scientific principles, strategies, and
approaches associated with medical device validation that are useful to practitioners. We intend this
column to be a valuable resource for daily work
applications. The key objective for this column:
Useful information.
Reader comments, questions, and suggestions are
needed to help us fulfill our objective for this column. Please send your comments and suggestions to
column coordinator John E. Lincoln at jel@jelincoln.
com or to journal coordinating editor Susan Haigney
at shaigney@advanstar.com.
For more Author
information,
go to
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•Predicate devices are described.
•New devices may be marketed if they are substantially equivalent to a marketed predicate device
based on their intended use, design, materials,
and other factors.
•Submission requirements for devices are
discussed.
•Combination products may be composed of any
combination of device, drug, and or biologic.
•The Special 510(k) Device Modification and the
Abbreviated 510(k) are alternate approaches
to demonstrating substantial equivalence in
medical devices.
KEY POINTS
INTRODUCTION
The following key points are discussed:
•Medical device companies must by law meet certain US Food and Drug Administration requirements before marketing a new or substantially
modified (physically or in labeled/intended use)
device in the US.
•Devices are generally defined. Devices may
include associated components and software.
•Devices are classified based on risk to the patient.
Classification determines the required level of
control and submission requirements.
•Manufacturers must go through one of two
evaluation processes: premarket notification
(510[k]), unless exempt, or premarket approval
(PMA), a much more involved process.
•The majority of medical devices are reviewed
for commercial distribution in the US by the
premarket notification (510[k]) process.
Medical device companies must by law meet certain
requirements before marketing a new or substantially modified (physically or in labeled/intended
use) device in the US. For any device, except the
most benign (generally US FDA Class 1) or the newest technology (generally Class 3), this means the
manufacturer or specification developer must seek
regulatory clearance for any new or substantially
changed device prior to marketing by means of a
Premarket Notification, or 510(k), submission.
The 510(k) system is currently one of the areas
under review by the US Food and Drug Administration to ensure it does not allow high-risk products
to enter or remain in the US market.
HISTORY
Medical products manufactured in the United States
for sale in the US, or manufactured outside the US
[
ABOUT THE AUTHOR
John E. Lincoln is principal of J.E. Lincoln and Associates (www.jelincoln.com), a global consulting
company with more than 29 years experience serving US FDA-regulated industries. He may be reached
by e-mail at jel@jelincoln.com or by phone (toll free) at 888.882.4655.
of
Validation T echnology [Summer 2010]
iv thome.com
John E. Lincoln, Coordinator.
and shipped into the US for sale, and meeting the
definition of a device under section 201(h) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act,
or “the Act”) are regulated by FDA. Medical devices
are subject to general controls and other controls in
the FD&C Act (1). “General controls” of the FD&C
Act are the baseline requirements that apply to all
medical device manufacturers. Unless specifically
exempted, medical devices must be the following:
•Properly labeled and packaged
•Cleared for marketing by FDA
•Consistent in meeting their labeling (intended
use) claims
•Manufactured under the current good manufacturing practices (CGMPs), also known as the
Quality Systems (QS) Regulation, 21 CFR 820,
a mandated quality assurance system (2).
This regulation is to assure device safety and
effectiveness. To fulfill provisions of the Act, FDA
develops and promulgates rules to regulate devices
intended for human use. These rules regulate various
aspects of the design, clinical trials and evaluation
(where required), manufacturing, packaging, labeling
(including promotional information), commercial
distribution, and post-market surveillance of devices.
These regulations are published in the Federal Register.
Final regulations are codified annually in the Code of
Federal Regulations (CFR). Most device regulations
are in Title 21 CFR Parts 800 to 1299.
The definition of a device appears in section
201(h) of the Act (not the CFR). A device is: “...an
instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar
or related article, including a component, part, or
accessory, which is:
•Recognized in the official National Formulary,
or the United States Pharmacopeia, or any supplement to them
•Intended for use in the diagnosis of disease or
other conditions, or in the cure, mitigation,
treatment, or prevention of disease, in man or
other animals, or
•Intended to affect the structure or any function
of the body of man or other animals, and which
does not achieve any of its primary intended
purposes through chemical action within or on
the body of man or other animals and which
is not dependent upon being metabolized for
the achievement of any of its primary intended
purposes...” (1).
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Certain components such as blood tubing sets,
major diagnostic x-ray components, and stand-alone
software are regulated by FDA as finished devices
because they are accessories to finished devices
and meet the Act’s definition of a device. Software
that is to be marketed separately to enhance the
performance of a device is regulated as an accessory to the device that poses the greatest risk to
the patient. For example, software used with a
Class 3 device may be regulated as Class 3. The
manufacturer of accessories is subject to the medical
device regulations when the accessory is labeled and
marketed separately from the primary device for
a health-related purpose to a hospital, physician,
or other end-user.
As mentioned, FDA has established classifications
for the different generic types of devices, based on
the risk to the population. Thus, the level of control
necessary to assure the safety and effectiveness varies
with the class of the device.
FDA’s three classes (not the European Union’s
Medical Device Directive) and their respective
requirements are as follow:
•Class 1—General Controls (good manufacturing
practices [GMPs]; usually no 510[k] required)
•Class 2—General Controls and Special Controls
(510[k] required)
•Class 3—General Controls and Premarket
Approval (PMA).
General controls that apply to all medical devices
include the following:
•Prohibition of adulteration, section 501
of the Act
•Prohibition of misbranding, section 502
of the Act
•Banned devices, section 516 of the Act
•Notification; and repair, replacement or
refund; section 518 of the Act
•Records and reports, section 519 of the Act
•Restricted devices, section 520 of the Act.
General controls contain requirements for device
manufacturers or other designated individuals to
do the following:
•Register their establishment with FDA
(form FDA 2891)
•List their devices with FDA (form FDA 2892)
•Comply with labeling regulation (21 CFR Part
801, 809, or 812)
•Submit a premarket notification (510[k]) to FDA
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•Design and produce devices under GMP, now
designated quality system regulations (QS Regulations; 21 CFR Part 820).
To market a medical device in the US, manufacturers must go through one of two evaluation processes:
premarket notification (510[k]), unless exempt, or
premarket approval (PMA), a much more involved
process. 510(k)s are “cleared” for sale by FDA. PMAs
are “approved.” The majority of medical devices are
reviewed for commercial distribution in the US by the
510(k) process. In certain instances, devices legally
on the market prior to May 28, 1976 may not require
either a 510(k) or PMA submission (this is under current review by FDA). This exclusion does not apply to a
“me-too” device, newly manufactured by another company, but only to those devices marketed prior to 1976,
and still being marketed by the same company while
remaining basically unchanged (in the device, manufacturing process, and method of sterilization).
The Medical Device Amendments of 1976 mandate the submission of a premarket notification to
FDA. The purpose of a 510(k) is to demonstrate that
the medical device to be marketed is substantially
equivalent (SE) to a legally marketed device that was
or is currently on the US market (i.e., having a proven
field record of safety and efficacy).
PREDICATES
Proving SE requires the location and identification
of a predicate device. A predicate device is defined
as follows:
•Was legally marketed in the US prior to May
28, 1976 (pre-amendment; “grandfathered”
devices) and has not been significantly changed
or modified since then; and for which a regulation requiring a PMA application has not been
published by FDA
•Which has been reclassified from Class III
to Class II
•Which itself has been found to be substantially
equivalent through the 510(k) process after
May 28, 1976.
Listings and descriptions of such devices can be
found in the CFR database on the web.
The term predicate device only applies to devices
in categories subject to 510(k) review, and not devices
requiring premarket approval, because the basis of
the PMA is not a comparison of one device to another
(preexisting device) as it is in a 510(k).
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SUBSTANTIAL EQUIVALENCE
A device is substantially equivalent (SE) if, in comparison to a legally marketed (predicate) device, it
has the following:
•Same intended use as a predicate
•Same technological characteristics as the
predicate device;
or has the following:
•Same intended use as a predicate
•Different technological characteristics;
and the following information is submitted to FDA:
•Does not raise new questions of safety and
effectiveness
•Demonstrates that the device is as safe and as
effective as the legally marketed device.
Different technological characteristics include, but
are not limited to, changes in materials, design, energy
sources, and principles of operation.
Substantial equivalence does not mean the devices
must be identical. SE is established with respect to
the following:
•Intended use
•Design
•Energy used or delivered
•Materials
•Performance, safety, effectiveness
•Labeling
•Biocompatibility
•Standards
•Other applicable characteristics.
If FDA finds the device to be SE, FDA will send
the manufacturer a marketing clearance letter (not
an “approval”), referred to as an “SE letter,” and the
device may be marketed as described in the 510(k).
The goal of FDA is to submit such a finding, if the
device is truly SE and the submission is basically complete, in approximately 90 days from date of receipt
of the 510(k) submission from the submitter. Complexity of the device, inaccuracies or omissions in the
submission, or similar, can result in delays or a “refuse
to accept” determination on the part of FDA. In 2010,
FDA was looking at the possibility of revoking 510(k)s
for products found to have greater risk in use than
what was indicated or reviewed in the 510(k).
If FDA finds the device to be not substantially equivalent (NSE), then the manufacturer will be so notified.
The manufacturer then has the following options:
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John E. Lincoln, Coordinator.
•Resubmit another 510(k) with new (not restated)
information
•Petition FDA requesting the device be reclassified
into Class I or II, as described in section 513(f)
of the Act, if warranted
•Submit a PMA.
Manufacturers may not place their device into US
commerce until they receive a marketing clearance
(SE letter) from FDA. A past misconception that a
device may be placed on the market after 90 days have
elapsed, whether or not formal notice of clearance has
been received from FDA, is not correct.
SUBMISSION REQUIREMENTS
According to 21 CFR section 807.81, a premarket notification submission is required for the following:
•A device that requires a 510(k) clearance is
planned to be marketed for the first time by a
medical device firm who is required to register
•An existing device with 510(k) clearance or a
pre-amendment device is being marketed and is
to be changed or modified in a way that could
significantly affect its safety or effectiveness (e.g.,
significant change or modification in design,
material, chemical composition, energy source,
or manufacturing process)
•A major change or modification in the intended use for a pre-amendment or 510(k) device
is claimed.
A submission is not required if the following:
•Device has been exempted by the classification regulations in 21 CFR Parts 862-892. Most
Class I devices are exempt (subject to limitations on exemptions)
•Device requires a PMA
•Device was legally distributed by the same
firm in the US prior to May 28, 1976, provable
and documented (i.e., is pre-amendment or
grandfathered) and it has not been significantly
changed since then
•Rights to market a pre-amendment or 510(k)
cleared device has been acquired from another
firm, and the:
•Device has not been significantly changed
since then
•New owner does not make any changes to
the device
•Device is being distributed under a “Private
Label” (i.e., a pre-amendment device or a
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device with a valid 510(k) that is being placed
into commercial distribution for the first time
by a distributor under their own name or a
re-packager who places their own name on a
device), provided no changes are made to the
device, its indications for use, and it is not
further processed (e.g., sterilized) in a manner
not dealt with in the existing 510(k).
CHANGES AND MODIFICATIONS
Changes requiring a new 510(k) are the source of
much confusion in industry. It helps to remember
that FDA considers the manufacturer to be the best
qualified to make this decision and, hence, holds the
manufacturer responsible to make the proper determination. FDA further requires that the changes be
tightly controlled (per the QS Regulations and GMPs),
documented, including a written rationale for not submitting a 510(k). Such analysis could be incorporated
in a company’s change order (CO) system.
WHO SUBMITS A 510(K)?
FDA does not specifically state who may apply for a
510(k). FDA does, however, specify what actions require
the submission of a 510(k). These are the following:
•Domestic manufacturers introducing a device to
the US market
•Specification developers introducing a device to
the US market
•Foreign manufacturers and exporters or US representatives of foreign manufacturers or exporters
introducing a device to the US market, which can
include distributors of imported medical devices
•Re-packers or re-labelers who make labeling changes (intended use, claims), other than in name, or
whose operations significantly affect the device
•Re-processors who collect used single-use devices, manufactured by other companies, clean,
repair, package, re-sterilize, and resell them
under their own label.
Only one firm can hold the rights to a specific
510(k), since the 510(k) applies to a specific device.
FDA does not track the resale of 510(k)s, and/or who
currently owns the 510(k).
COMBINATION PRODUCTS
Combination products may be composed of any combination of device, drug, and or biologic. Prior to
any submission, contact FDA (start with the Division
of Small Manufacturers, International and Consumer
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Device Validation Forum.
Assistance [DSMICA]) and obtain a determination as
to the primary mode of action of such a combination
product, usually based on its intended use, and/or
the highest risk to safety or efficacy component.
FDA has inter-center agreements between Center for
Devices and Radiological Health (CDRH), Center
for Biologics Evaluation and Research (CBER), and
Center for Drug Evaluation and Research (CDER),
available through DSMICA. These agreements outline which agency has the authority for reviewing
combination products (3).
DIFFERENT 510(K)S
The guidance document entitled New 510(k) Paradigm—Alternate Approaches to Demonstrating Substantial
Equivalence in Premarket Notifications, was published
by the FDA’s CDRH, effective March 20, 1998. New
510(k) Paradigm presents device manufacturers with
additional and optional approaches to facilitate (i.e.,
speed up), review, and obtain marketing clearance for
devices subject to 510(k) requirements, as follows:
•The “Special 510(k) Device Modification”
option utilizes certain aspects of the Quality
System Regulation, and a company’s previous
510(k) submission(s)
•The “Abbreviated 510(k)” option relies on the
use of guidance documents, special controls,
and recognized standards
•The “Traditional 510(k)” method has also been
retained and is still required to be used if either
of the above two new option’s requirements
can’t be met (4).
SPECIAL 510(K): DEVICE MODIFICATION
The Safe Medical Devices Act of 1990 required preproduction design controls. Consequently, a design
control requirement component was added to the
GMPs as part of the new QS regulations (21 CFR
820.30, Subpart C), effective June 1, 1997. This
requires device manufacturers to have systems
for the management of design and development,
including documentation of design inputs, risk
analysis, design output, test procedures, verification
and validation procedures, and documentation of
formal design reviews. In this process, the manufacturer must ensure that design input addresses
intended use and user needs. The manufacturer
must define and document design output (including
specifications and other device master record [DMR]
elements) to allow evaluation of conformance to
design input requirements.
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The new design control requirements require the
manufacturer to conduct verification and validation
studies the same as have been required under “traditional” 510(k) submissions. In view of this new
requirement, FDA believes it can forego a detailed
review of such underlying data. As a result, for some
device modifications, data generated under the new
design control requirements may be retained by the
manufacturer, and is not required to be submitted
as part of a “Special 510(k): Device Modification”
submission for a determination of SE.
As always, some changes, if minor, do not require
the submission of a new 510(k). Rumor to the contrary, there is no mechanism to file an “update” or
“supplement” to a 510(k). However, when the manufacturer decides that a change, or the cumulative
effect of several changes over time, now require a
new submission, and the changes do not affect the
intended use, the safety or effectiveness issues, or
the fundamental scientific technology (operating
principle(s), mechanism of action), then a “Special
510(k): Device Modification” may be submitted. The
submission may contain only summary information
resulting from the design control process, which can
serve as the basis for clearing the application.
A manufacturer who is intending to modify their
own legally marketed device will conduct the risk
analysis, and the necessary verification and validation
activities, to demonstrate that the design outputs of
the modified device meet the design input requirements. Once demonstrated, the “Special 510(k):
Device Modification” may be submitted. The submission will maintain the basic content format of
the traditional 510(k), except the “Special 510(k)...”
must include a reference to the existing and cleared
510(k) number and a “Declaration of Conformity”
to design controls.
The QS regulations (GMPs) require periodic internal audits to assure conformance to design controls.
A manufacturer can use a third party (e.g., consultant) to provide a supporting assessment, and provide the manufacturer with a statement to this effect.
While the “Declaration of Conformity” is signed
by the manufacturer, the statement from the third
party is retained in the DMR. However, the ultimate
responsibility for adherence to design control rests
with the manufacturer.
It is the intention of the Office of Device Evaluation
(ODE) to process Special 510(k)s within 30 days of
receipt by the Document Mail Center, as opposed to
the usual 90 plus days for a traditional 510(k).
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John E. Lincoln, Coordinator.
ABBREVIATED 510(K)
For many devices there exists device-specific documents that define regulatory guidance and scientific
expectations to industry to provide reasonable assurance of the device’s safety and effectiveness. They
include the following:
•Guidance documents from FDA
•Special controls, such as performance standards,
post-market surveillance, patient registries, development and dissemination of guidelines, recommendations, and other appropriate actions
•Individual consensus standards (published
national and international standards, formally
recognized by FDA).
When such standards exist and apply, device manufacturers may choose to submit an Abbreviated 510(k).
In addition to the basic format and general information required by the traditional 510(k), the Abbreviated 510(k) submission must include the following:
•A summary report describing how the guidance
document/special control, et al., were used during device development and testing; and outlining conformances to and any deviations from
the standard
•A declaration of conformity to the recognized
standard.
The manufacturer may use a third party (consultant) to assess conformance with the recognized
standard, and must maintain a “statement of conformity” as part of the DMR. The manufacturer makes
the “declaration of conformity” submitted with the
Abbreviated 510(k) and still retains responsibility.
The advantage is that if the application is accepted as
an “Abbreviated 510(k)” submission, this will allow
an expedited review by ODE.
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REFERENCES
1. Federal Food, Drug, and Cosmetic Act, Sec. 201. [21
U.S.C. 321] Chapter II—Definitions.
2. FDA, 21 CFR 820, Title 21 Food And Drugs, Chapter I
Food And Drug Administration, Department Of Health
And Human Services, Subchapter H Medical Devices,
Part 820 Quality System Regulation, 61 Federal Register
52654, Oct. 7, 1996.
3. FDA, Premarket Notification 510(k)—Regulatory Requirements for Medical Devices, the US Department of Health
and Human Services, Public Health Service, Food and
Drug Administration.
4. FDA, New 510(k) Paradigm—Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications, CDRH, effective March 20, 1998. JVT
ARTICLE ACRONYM LISTING
CBER FDA Center for Biologics
Evaluation and Research
CDERFDA Center for Drug
Evaluation and Research
CDRH FDA Center for Devices and
Radiological Health
CFR
Code of Federal Regulations
DSMICAFDA Division of Small Manufacturers,
International and Consumer Assistance
EU MDDEuropean Union’s Medical Device
Directive, Council Directive 93/42/
EEC of 14 June 1993, as amended
NSENot Substantially Equivalent
ODEFDA Office of Device Evaluation
QSQuality System
SESubstantial Equivalence or
Substantially Equivalent
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