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THE COMMITTEE ON HUMAN RESEARCH
UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES
INVESTIGATIONAL DEVICES
(June 2004, Revised May 2006, September 2007, February 2008)
Brief Overview: Investigational
Devices
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The Food
and Drug Administration (FDA) regulates research involving medical devices as well as
all aspects of device manufacturing, marketing, and distribution
[Code of Federal Regulations Title 21, parts 800-1299]. |
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For most studies involving devices, an investigator
or sponsor must obtain an Investigational Device Exemption (IDE)
from the FDA. |
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The responsible branch of the FDA is the Center
for Devices and Radiological Health (CDRH). |
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A device is considered investigational if
either condition applies: |
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the device is not approved for marketing in the United States |
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the device is approved for marketing but is being clinically
evaluated for a new indication |
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All device studies involving
human subjects must be submitted to the Committee of Human Research
for review and approval before the investigation can begin. |
When is an Investigational
Device Exemption (IDE) Required?
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Testing an Unapproved Significant
Risk Device: An investigational device exemption (IDE)
from the FDA is required to do a clinical study of an unapproved
device that
poses a significant risk to subjects.
The majority of IDE studies are conducted to collect safety and
effectiveness data used to support Premarket Approval
(PMA) applications submitted to the FDA. |
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Testing a Legally Marketed
Device for a New Indication: IDE regulations apply to significant
risk studies testing an FDA-approved device for a new indication.
IMPORTANT NOTE: An IDE
is not required for off-label use of an FDA-approved device
used by a physician in the practice of medicine.
Example: Significant risk
(SR) studies involve implantable devices such as cardiac pacemakers,
orthopedic
implants, and stents. SR studies can also involve products
not introduced into the body, such as computer software used
for prenatal risk evaluation. Each of these studies would require
an IDE.
For more informatin please see HRPP Guidance on Significant and non-significant Risk Devices.
Example: A legally marketed coronary stent
would be considered an investigational device and would require
an IDE if used as part of a study to collect safety and effectiveness
data for treating conditions involving other vascular sites.
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When is an Investigational
Device Exemption (IDE) Not Required?
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Testing A non-significant Risk
(NSR) Device:
An IDE is not needed for research use of some non-significant
risk devices or devices that are substantially
equivalent to currently marketed devices. |
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CHR review and approval are required for all
NSR studies. |
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The FDA authorizes institutional review boards
to conduct a risk assessment of all proposed non-significant risk
studies. |
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Study approval is dependent on the investigator
supplying the CHR with sufficient information, generally provided
by the study sponsor, regarding the device and its intended use.
IMPORTANT NOTE: Although FDA approval is not required, the
agency can assume study jurisdiction at any time deemed necessary.
Example: Nonsignficant risk devices include
daily wear contact lenses and associated care products; conventional
gastroenterology and urology endoscopes; externally worn monitors
for insulin reactions; general catheters (biliary, urological);
and, nonimplantable electrical incontinence devices.
For more information please see HRPP Guidance on Significant and non-significant Risk Devices. |
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Practice
of Medicine: A physician
can use a legally marketed device without CHR approval for any
condition or disease within a “legitimate healthcare practitioner-patient
relationship”. However, the results of an off-label use of
a medical device cannot be presented as research. |
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Specific IDE-Exempt Studies: Federal regulations describe the
following IDE-exempt studies. |
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Please review the HRPP information sheet, Exemptions from IDE Requirements for a complete list of all types of investigations which are exempt from FDA IDE requirements, according to 21 CFR 812.2. |
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The more common IDE-exempt investigations submitted to the CHR meet the following criteria: |
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Investigations conducted with legally marketed
devices used according to labeling. |
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Studies using in vitro diagnostics labeled for “research
purpose only” as per regulations [21
CFR 809.10(c)] and if
the testing: |
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is noninvasive; |
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does not require invasive sampling procedure
that presents significant risk; |
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does not introduce energy into a subject; and |
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is not used as a diagnostic procedure without
confirmation by another medically established diagnostic product
or procedure; |
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Additional guidance
on studies using in vitro diagnostics is available. |
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CHR Application Requirements
The CHR application process is described on the CHR
Website.
Key information that should be submitted for device studies is listed below.
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For Significant Risk Studies include
all of the following that are available: |
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An IDE number – the CHR will not issue final
approval until the IDE number is reported to and verified by the CHR. Verification can be accomplished by providing a copy of the sponsor's protocol with the IND number listed, or by submitting correspondence from the sponsor or FDA indicating the IND number for the study. However, the CHR
will review the research before the IDE application is submitted to the
FDA. |
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Investigator’s Brochure |
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Directions for use, typically provided by the manufacturer |
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Device labeling consistent with federal regulations
[21
CFR 812.5]. |
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Clinical protocol [also known as “sponsor protocol” or “multicenter
protocol”]. By any name, this document should describe the methodology
to be used and offer an analysis that the study is scientifically sound. |
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An explanation of the device cost as determined by the
reimbursement
category provided by FDA with each approved IDE. This information
is needed for the consent form (see below). |
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Clearance from the Radiation
Safety Committee for radiation-emitting
devices. |
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For Non-Significant Risk Studies include
all of the following that are available: |
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The CHR’s Non-Significant
Risk Supplement with
adequate justification that the device, and/or its proposed use, does not
pose a significant risk to subjects. |
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Include any detailed information from the sponsor,
such as a description of the device and how it is used. |
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Diagrams and/or in situ photographs of the device are
very useful. |
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Directions for use, typically provided by the sponsor
or manufacturer. |
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Device labeling consistent with federal regulations
[21 CFR 812.5]. |
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Clinical protocol [also known as “sponsor protocol” or “multicenter
protocol”]. By any name, this document should describe the methodology
to be used and offer an analysis that the study is scientifically sound. |
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An explanation of the device cost. non-significant
risk devices are placed in Category B and are most likely eligible for
reimbursement. See the reimbursement
category overview provided by the FDA.
IMPORTANT NOTE: If the CHR determines
that the proposed non-significant risk study is actually a significant
risk study, the sponsor must submit
to the FDA a report of the CHR findings within 5 working days
after learning of the CHR’s determination [21 CFR 812.150(9)]. |
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Consent Forms
All medical device studies involving human subjects require informed
consent. The CHR provides template
forms for informed consent with the
required elements. Investigators should include the following key points
within the sections noted below:
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Adverse Event Reporting
Adverse events associated with research participation must be reported
expeditiously to both the Committee on Human Research (CHR) and to the
FDA.
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Investigator’s
Responsibilities: All
investigators have an obligation to report certain adverse events
(AE) directly to the IRB. |
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Please review the CHR
Guidelines on Adverse Event Reporting for a detailed description of the CHR reporting requirements. |
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Under IDE regulations there are additional and separate
federal requirements for reporting adverse events to the FDA. When
the study sponsor holds the IDE, investigators need to report all
adverse events to the sponsor and the sponsor will submit appropriate
reports to the FDA. |
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Investigator-Sponsor Responsibilties: Investigators
who hold an IDE have responsibilities for reporting adverse events
associated with the investigational device. In addition to reporting
to the CHR, an investigator-sponsor must directly report the following
adverse event information to the FDA: |
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Unanticipated adverse events investigated under
a sponsor’s monitoring requirements [21 CFR 812.46(b)], must
be reported to FDA within 10 working days after the sponsor receives
notice of the effect. |
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Types of IDE Applications
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Commercial IDE: An IDE application
submitted by a sponsor seeking FDA clearance to market a medical
device. |
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Investigator-Initiated IDE: By submitting
an IDE application to the FDA and conducting the clinical investigation,
a physician takes on the responsibilities
of both “sponsor” and “investigator.” |
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Emergency Use IDE: This
is an exception to investigational device regulations permitting
the one-time treatment of one patient
per institution without prior FDA approval. |
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There are strict reporting requirements and every
effort must be made to obtain prior authorization from the CHR. |
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The emergency use of an investigational device must
meet all of the following criteria: |
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the patient has a life-threatening or severely debilitating
condition, and |
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there are no other available treatments, and |
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there is not sufficient time for prior IRB review and approval. |
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IMPORTANT NOTE: Research
may not be conducted under an emergency use IDE and subsequent
use(s) of the investigational device require
prior CHR review and approval. For more information, please review
the CHR Emergency Use Guidelines. |
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Additional IDE Mechanisms
Allowing Expanded Access: There are several regulatory mechanisms
that allow expanded
access to investigational medical devices
while clinical studies and/or FDA review are on-going. Because
FDA is primarily concerned with protecting public safety, the
number of patients who can be treated under these special access
mechanisms is limited and generally determined by the existence
of sufficient safety and efficacy data. A brief discussion of
each mechanism follows.
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Compassionate Use IDE: Under an existing IDE, the
FDA may allow treatment of a small number of seriously ill patients
who have no acceptable alternatives. The FDA requires the sponsor/investigator
to supply a supplement to an existing IDE justifying the compassionate
use.
IMPORTANT NOTE: Compassionate use requires FDA review and approval and concurrence of a CHR
Chair before treatment can be initiated. The study involving the existing IDE must already be approved by the CHR.
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Treatment IDE: If FDA has reviewed sufficient
safety and efficacy data obtained under an existing IDE, wider
access to an unapproved device may be granted to desperately
ill patients under Treatment
IDE regulations.
IMPORTANT NOTE: Prior
FDA and CHR review and approval are required. |
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Continued Access: After the completion of a controlled
clinical trial, a Supplement to an existing IDE can be submitted
and the FDA may allow continued
access to the device provided
there are no safety concerns. The Continued Access Policy allows
access to promising devices while the marketing application is
being prepared by the sponsor or reviewed by the FDA.
IMPORTANT NOTE: Prior FDA and CHR review and approval are required. |
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Timing the IDE Submission
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Pre-IDE Process:
The FDA encourages applicants to communicate with the reviewing
division of the Office of Device Evaluation (ODE) prior to the
submission of the original IDE application. More information
about the Pre-IDE
Process is available. |
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The IDE Submission: The IDE submission to the FDA
and the CHR application should be initiated at the same time. The
FDA has 30 days to review the IDE application. Likewise, the CHR
makes every effort to review an application within a 30-day window,
but a longer review period is often necessary. An investigator
cannot initiate a clinical study until the FDA and CHR have granted
approval. |
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Responsibilities
of Investigators and Sponsors
While conducting significant risk and non-significant
risk device studies, investigators and sponsors have specific responsibilities.
The obligations span a broad range, including FDA and IRB approvals,
informed consent, study monitoring, and multiple reporting requirements.
Links to detailed information pertinent to each role are provided below:
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Control of Investigational Devices – Investigator
Responsibilities
Investigators conducting studies in which an investigational
device will be used must ensure adequate control of the device. Adequate
control and handling of investigational devices include all of the
following:
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The investigator must ensure
that the investigational device is used only in accordance with
the CHR-approved
protocol, the signed agreement, the investigational plan and applicable
FDA regulations. |
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The investigator must administer
the investigational device only to participants under the investigator’s
direct personal supervision or under the supervision of a sub-investigator
directly responsible to the investigator. |
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The investigator must not
supply the investigational device to any person not authorized
to receive
it. |
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The investigation must maintain
the following accurate, complete, and current records relating
to the
investigator’s participation in an investigation: |
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Records of receipt, use or disposition
of a device that relate to: |
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The type and quantity of the device,
the dates of its receipt, and the batch number or code mark. |
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The names of all persons who received, used,
or disposed of each device. |
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Why and how many units of the device have
been returned to the sponsor, repaired, or otherwise disposed of. |
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If the investigation is terminated,
suspended, discontinued, or completed, the investigator must return
any unused supplies of the investigational device to the study
sponsor, or otherwise provide for disposition of the unused supplies
as directed by the sponsor. |
Sample
Investigational Device Accountability Log
Special Medical
Device Regulations
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Humanitarian
Device Exemption (HDE) |
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An HDE is a type of Premarket Application described
under the Safe Medical Devices Act (SMDA) of 1990 and allows FDA
to grant an exemption from the effectiveness provisions of the
Premarket Approval (PMA) regulations. Devices approved under an HDE are referred to as Humanitarian Use Devices (HUD). The provisions for obtaining
an HDE are: |
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the device is designed to treat or diagnose a disease or condition
that affects fewer than 4,000 individuals per year in the U.S.; |
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the device is not available otherwise, and there is
no comparable device available to treat or diagnose the disease
or condition; and |
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the device will not expose patients to unreasonable
or significant risk, and the benefits to health from the use outweigh
the risks. |
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Treatment under an HDE is not considered research,
but the FDA requires CHR review prior to use. The CHR requires
a standard application and use of a consent form similar to research
consent. |
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The CHR has posted a sample consent form for Humanitarian Use Devices. |
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Drug-Device Combination
Products: If an investigator is interested in evaluating a combination
product, the following links may be useful: |
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The Office
of Combination Products (OCP) was created
in 2002 to facilitate the review process for combination products
by coordinating interactions between reviewing branches. |
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As an aide to sponsors, the OCP provides applicable
guidance
documents for combination products. |
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Some recent combination product approvals include: |
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drug-eluting coronary stents; |
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spinal fusion putty; and, |
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an influenza vaccine administered via an intranasal delivery
device. |
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A complete listing of recently
approved combination products is available. |
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Import/Export of
Investigational Devices
A complete overview
of medical device import/export regulations is provided by the CDRH. Clinical investigators should
be aware that FDA does not recognize regulatory approvals from other
countries; therefore, an imported medical device must meet all FDA
requirements.
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The IDE sponsor must
be located in the United States. |
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Anyone who intends to import an investigational device
takes on the responsibilities of a sponsor. |
Definitions and
Quick Links
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Significant
and Non-Significant Risk Devices: See HRPP Guidance on Significant and Non-Significant Devices. |
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Types of Marketing Applications |
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Premarket
Notification [510(k)] applies to Class
I, Class II, and some Class III devices. |
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A sponsor must demonstrate “substantial
equivalence,” meaning that the new device is as safe and
effective as the predicate device(s). |
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New guidelines describing streamlined 510(k)
options are available. |
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Clinical studies using 510(k) devices may be subject to IDE regulations.
Prior FDA and CHR approval are required. |
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Premarket
Approval (PMA) has more stringent requirements
for high risk Class III devices.
In most cases an investigational device exemption (IDE) is required
to
clinically evaluate devices subject to PMA regulations. |
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Humanitarian Device Exemption
(HDE) is part of
the FDA Modernization Act aimed at encouraging device development
for conditions with fewer than 4,000 patients. |
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Product Development Program
(PDP) is part of the “reengineering” of
the PMA process underway and aims to facilitate bringing Class
III devices to market faster. Interested parties are encouraged
to contact FDA:
PDP Reengineering Team
Center for Devices
and Radiological Health (HFZ-150)
9200 Corporate Blvd
Rockville MD 20850 |
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Device
Classification: The
level of regulatory controls placed on a medical device is determined
by the risk classification. Most research reviewed by the CHR involves
significant risk, Class III devices. The FDA provides an overview
of the risk-based
classification scheme. To help determine device
classification, regulatory controls, and exemptions, the Center
for Devices and Radiological Health (CDRH) maintains: |
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A searchable classification
database containing
information about all approved Class I, Class II, and Class III
devices. |
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A device listing categorized by medical specialty |
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A listing of Class I and Class II devices deemed
exempt from Premarket Notification 510(k) regulations. |
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Guidance for devices that emit
radiation. |
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Resources
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