Biomedical Engineering Reference
In-Depth Information
study endpoints, and statistical analysis plan. In
addition to FDA oversight, clinical trials are also
overseen by local Investigational Review Boards
(IRBs) at each institution participating in the clinical
trial. If an IDE is approved by the FDA, the clinical
trial can proceed.
After the trial is finished (a process that typically
takes 3
e
4 years for many Class III orthopedic and
spinal devices that include clinical studies with 2-
year primary endpoints), an application for PMA can
be submitted. These are the most complex submis-
sions, often consisting of multiple volumes, which
summarizes all of the information that was provided
in the IDE on preclinical safety, but also a complete
analysis of the results from the clinical trial. If
a device is “first-of-its-kind” or highly novel in some
way, the FDAwill convene a panel of outside experts
to review the data and give their (nonbinding)
recommendation regarding the safety and effective-
ness of the device to the agency. Otherwise, the FDA
reviews all of the data internally and makes the
decision whether to take the device to panel for
questions not previously addressed for similar
devices before deciding whether to approve or not
approve the new device.
Clearly, the 510(k) premarket notification pathway
is a less burdensome process for getting devices to
market in the United States than the PMA pathway,
but the former can only be used for devices that are
low to medium risk and/or are similar to devices
already on the market with a long history of clinical
success. For comparison purposes, companies
submitting a 510(k) premarket notification will pay
a user fee of $4348 to the FDA (for FY2011), and the
CDRH reviews the majority of these submissions
within 90 days. The CDRH typically receives
3000
e
4000 submissions of 510(k) per year, and in
FY2008, the average review time was 64 days. In
contrast, the user fee for a PMA submission is
$236,298 (for FY2011) and the CDRH's goal is to
review the application within 180 days. The FDA
typically receives approximately 50 original PMA
applications per year, but can receive upward of 600
“PMA Supplements” that provide updates or addi-
tional information to existing PMAs. In 2009, the
average FDA review time for PMA applications was
145 days with a final decision. Finally, the CDRH
receives approximately 220 IDEs each year, and is
required to review these in 30 days or less, but
manufacturers are not charged a user fee to submit
an IDE
[6]
.
Note that the average review times listed above do
not take into account the fact that reviews often
involve multiple rounds of correspondence between
the agency and the sponsor. Each time the FDA sends
requests for more information to a company, it “stops
the FDA clock” and the time that it takes the sponsor
to respond is not counted towards the FDA's review
time. Device manufacturers should realize, for
example, that many PMA applications take closer to
a year between the time they are first submitted and
when approval is finally granted. Note also that the
user fees are drastically reduced for small businesses
(defined as those having less than $100 million in
gross receipts or sales in the most recent tax year) to
$2174 for a 510(k) and $59,075 for a PMA in
FY2011.
17.7 Content of an FDA
Application
Because of the different device classifications and
types of FDA submissions mentioned above, each
application to the FDA may contain different types
and amounts of information covering different
aspects of the device. In general, the Code of Federal
Regulations outlines the elements that each type of
FDA submission must contain, and the “Device
Advice” section of the FDA's website gives addi-
tional “plain-language” advice on what to include.
For example, a Traditional 510(k) submission must
include the required elements identified in 21 CFR
807.87 (“Information required in a premarket
notification submission”). Additionally, the CDRH
recommends that you follow the Traditional 510(k)
format provided in the guidance document, “Format
for Traditional and Abbreviated 510(k)s”
[7]
.
In discussing the definition of safety and effec-
tiveness for medical devices, 21 CFR 860.7 specifi-
cally states that the FDA must rely upon “only
valid
scientific evidence
to determine whether there is
reasonable assurance that the device is safe and
effective
.
for its conditions of use. [emphasis
added]” Valid scientific evidence is further described
in 21 CFR 860.7(c)(2) as “evidence from well-
controlled investigations, partially controlled studies,
studies and objective trials without matched controls,
well-documented case histories conducted by quali-
fied experts, and reports of significant human expe-
rience with a marketed device, from which it can
fairly and responsibly be concluded by qualified
