**CODE OF FEDERAL REGULATIONS**

**Title 21\--Food and Drugs**

**CHAPTER I\--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND
HUMAN SERVICES**

# 

PART 814---PREMARKET APPROVAL

OF MEDICAL DEVICES

Table of Contents

> 814.1 Scope.
>
> 814.2 Purpose
>
> 814.3 Definitions.
>
> 814.9 Confidentiality of data and information in a premarket approval
> application (PMA) file.
>
> 814.15 Research conducted outside the United States.
>
> 814.17 Service of orders
>
> 814.19 Product development protocol (PDP).
>
> 814.20 Application.
>
> 814.37 PMA amendments and resubmitted PMA\'s.
>
> 814.39 PMA supplements.
>
> 814.40 Time frames for reviewing a PMA.
>
> 814.42 Filing a PMA.
>
> 814.44 Procedures for review of a PMA.
>
> 814.45 Denial of approval of a PMA.
>
> 814.46 Withdrawal of approval of a PMA.
>
> 814.47 Temporary suspension of approval of a PMA.
>
> 814.80 General.
>
> 814.82 Postapproval requirements.
>
> 814.84 Reports.
>
> 814.100 Purpose and scope.
>
> 814.102 Designation of HUD status.
>
> 814.104 Original applications
>
> 814.106 HDE amendments and resubmitted HDE\'s.
>
> 814.108 Supplemental applications.
>
> 814.110 New indications for use.

814.112 Filing an HDE.

> 814.114 Timeframes for reviewing an HDE.
>
> 814.116 Procedures for review of an HDE.
>
> 814.118 Denial of approval or withdrawal of approval of an HDE.
>
> 814.120 Temporary suspension of approval of an HDE.
>
> 814.122 Confidentiality of data and information.
>
> 814.124 Institutional Review Board requirements.
>
> 814.126 Postapproval requirements and reports.

**Subpart A\--General**

Sec. 814.**1** Scope.

\(a\) This part implements section 515 of the act by providing
procedures for the premarket approval of medical devices intended for
human use.

\(b\) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21, unless otherwise
noted.

\(c\) This part applies to any class III medical device, unless exempt
under section 520(g) of the act, that:

(**1**) Was not on the market (introduced or delivered for introduction
into commerce for commercial distribution) before May 28, 1976, and is
not substantially equivalent to a device on the market before May 28,
1976, or to a device first marketed on, or after that date, which has

been classified into class I or class II; or

\(2\) Is required to have an approved premarket approval application
(PMA) or a declared completed product development protocol under a
regulation issued under section 515(b) of the act; or

\(3\) Was regulated by FDA as a new drug or antibiotic drug before May
28, 1976, and therefore is governed by section 520(**1**) of the act.

\(d\) This part amends the conditions to approval for any PMA approved
before the effective date of this part. Any condition to approval for an
approved PMA that is inconsistent with this part is revoked. Any
condition to approval for an approved PMA that is consistent with this

part remains in effect.

Sec. 814.**2** Purpose.

The purpose of this part is to establish an efficient and thorough
device review process-

\(a\) To facilitate the approval of PMA\'s for devices that have been
shown to be safe and effective and that otherwise meet the statutory
criteria for approval; and

\(b\) To ensure the disapproval of PMA\'s for devices that have not been
shown to be safe and effective or that do not otherwise meet the
statutory criteria for approval. This part shall be construed in light
of these objectives.

Sec. 814.**3** Definitions.

For the purposes of this part:

\(a\) Act means the Federal Food, Drug, and Cosmetic Act (sections
201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321-392)).

\(b\) FDA means the Food and Drug Administration.

\(c\) IDE means an approved or considered approved investigational
device exemption under section 520(g) of the act and parts 812 and 813.

\(d\) Master file means a reference source that a person submits to FDA.
A master file may contain detailed information on a specific
manufacturing facility, process, methodology, or component used in the
manufacture, processing, or packaging of a medical device.

\(e\) PMA means any premarket approval application for a class III
medical device, including all information submitted with or incorporated
by reference therein. \`\`PMA\'\' includes a new drug application for a
device under section 520(1) of the act.

\(f\) PMA amendment means information an applicant submits to FDA to
modify a pending PMA or a pending PMA supplement.

\(g\) PMA supplement means a supplemental application to an approved PMA
for approval of a change or modification in a class III medical device,
including all information submitted with or incorporated by reference
therein.

\(h\) Person includes any individual, partnership, corporation,
association, scientific or academic establishment, Government agency, or
organizational unit thereof, or any other legal entity.

\(i\) Statement of material fact means a representation that tends to
show that the safety or effectiveness of a device is more probable than
it would be in the absence of such a representation. A false affirmation
or silence or an omission that would lead a reasonable person to draw a
particular conclusion as to the safety or effectiveness of a device also
may be a false statement of material fact, even if the statement was not
intended by the person making it to be misleading or to have any
probative effect.

\(j\) 30-day PMA supplement means a supplemental application to an
approved PMA in accordance with Sec. 814.39(e).

\(k\) Reasonable probability means that it is more likely than not that
an event will occur.

\(l\) Serious, adverse health consequences means any significant adverse
experience, including those which may be either life-threatening or
involve permanent or long term injuries, but excluding injuries that are
nonlife-threatening and that are temporary and reasonably

reversible.

\(m\) HDE means a premarket approval application submitted pursuant to
this subpart seeking a humanitarian device exemption from the
effectiveness requirements of sections 514 and 515 of the act as
authorized by section 520(m)(2) of the act.

\(n\) HUD (humanitarian use device) means a medical device intended to
benefit patients in the treatment or diagnosis of a disease or condition
that affects or is manifested in fewer than 4,000 individuals in the
United States per year.

Sec. 814.**9** Confidentiality of data and information in a premarket
approval application (PMA) file.

\(a\) A \`\`PMA file\'\' includes all data and information submitted
with or incorporated by reference in the PMA, any IDE incorporated into
the PMA, any PMA supplement, any report under Sec. 814.82, any master
file, or any other related submission. Any record in the PMA file will
be available for public disclosure in accordance with the provisions of
this section and part 20. The confidentiality of information in a color
additive petition submitted as part of a PMA is governed by Sec. 71.15.

\(b\) The existence of a PMA file may not be disclosed by FDA before an
approval order is issued to the applicant unless it previously has been
publicly disclosed or acknowledged.

\(c\) If the existence of a PMA file has not been publicly disclosed or
acknowledged, data or information in the PMA file are not available for
public disclosure.

(d)(1) If the existence of a PMA file has been publicly disclosed or
acknowledged before an order approving, or an order denying approval of
the PMA is issued, data or information contained in the file are not
available for public disclosure before such order issues. FDA may,

however, disclose a summary of portions of the safety and effectiveness
data before an approval order or an order denying approval of the PMA
issues if disclosure is relevant to public consideration of a specific
pending issue.

\(2\) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the IDE that was
required to be filed in Docket Number 95S-0158 in the Dockets Management
Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm.
1-23, Rockville, MD 20857, for investigations involving an exception

from informed consent under Sec. 50.24 of this chapter. Persons wishing
to request this information shall submit a request under the Freedom of
Information Act.

\(e\) Upon issuance of an order approving, or an order denying approval
of any PMA, FDA will make available to the public the fact of the
existence of the PMA and a detailed summary of information submitted to
FDA respecting the safety and effectiveness of the device that is the

subject of the PMA and that is the basis for the order.

\(f\) After FDA issues an order approving, or an order denying approval
of any PMA, the following data and information in the PMA file are
immediately available for public disclosure:

\(1\) All safety and effectiveness data and information previously

disclosed to the public, as such disclosure is defined in Sec. 20.81.

\(2\) Any protocol for a test or study unless the protocol is shown to
constitute trade secret or confidential commercial or financial
information under Sec. 20.61.

\(3\) Any adverse reaction report, product experience report, consumer
complaint, and other similar data and information, after deletion of:

\(i\) Any information that constitutes trade secret or confidential
commercial or financial information under Sec. 20.61; and

\(ii\) Any personnel, medical, and similar information disclosure of
which would constitute a clearly unwarranted invasion of personal
privacy under Sec. 20.63; provided, however, that except for the
information that constitutes trade secret or confidential commercial or

financial information under Sec. 20.61, FDA will disclose to a patient
who requests a report all the information in the report concerning that
patient.

\(4\) A list of components previously disclosed to the public, as such
disclosure is defined in Sec. 20.81.

\(5\) An assay method or other analytical method, unless it does not
serve any regulatory purpose and is shown to fall within the exemption
in Sec. 20.61 for trade secret or confidential commercial or financial
information.

\(6\) All correspondence and written summaries of oral discussions
relating to the PMA file, in accordance with the provisions of Secs.
20.103 and 20.104.

\(g\) All safety and effectiveness data and other information not
previously disclosed to the public are available for public disclosure
if any one of the following events occurs and the data and information
do not constitute trade secret or confidential commercial or financial

information under Sec. 20.61:

\(1\) The PMA has been abandoned. FDA will consider a PMA abandoned if:

(i)(A) The applicant fails to respond to a request for additional
information within 180 days after the date FDA issues the request or

\(B\) Other circumstances indicate that further work is not being
undertaken with respect to it, and

\(ii\) The applicant fails to communicate with FDA within 7 days after
the date on which FDA notifies the applicant that the PMA appears to
have been abandoned.

\(2\) An order denying approval of the PMA has issued, and all legal
appeals have been exhausted.

\(3\) An order withdrawing approval of the PMA has issued, and all legal
appeals have been exhausted.

\(4\) The device has been reclassified.

\(5\) The device has been found to be substantially equivalent to a
class I or class II device.

\(6\) The PMA is considered voluntarily withdrawn under Sec. 814.44(g).

\(h\) The following data and information in a PMA file are not available
for public disclosure unless they have been previously disclosed to the
public, as such disclosure is defined in Sec. 20.81, or they relate to a
device for which a PMA has been abandoned and they no longer represent a
trade secret or confidential commercial or financial information as
defined in Sec. 20.61:

\(1\) Manufacturing methods or processes, including quality control
procedures.

\(2\) Production, sales, distribution, and similar data and information,
except that any compilation of such data and information aggregated and
prepared in a way that does not reveal data or information which are not
available for public disclosure under this provision is available for
public disclosure.

\(3\) Quantitative or semiquantitative formulas.

Sec. 814.**15** Research conducted outside the United States.

\(a\) A study conducted outside the United States submitted in support
of a PMA and conducted under an IDE shall comply with part 812. A study
conducted outside the United States submitted in support of a PMA and
not conducted under an IDE shall comply with the provisions in paragraph
(b) or (c) of this section, as applicable.

\(b\) Research begun on or after effective date. FDA will accept studies
submitted in support of a PMA which have been conducted outside the
United States and begun on or after November 19, 1986, if the data are
valid and the investigator has conducted the studies in conformance

with the \`\`Declaration of Helsinki\'\' or the laws and regulations of
the country in which the research is conducted, whichever accords
greater protection to the human subjects. If the standards of the
country are used, the applicant shall state in detail any differences
between those

standards and the \`\`Declaration of Helsinki\'\' and explain why they
offer greater protection to the human subjects.

\(c\) Research begun before effective date. FDA will accept studies
submitted in support of a PMA which have been conducted outside the
United States and begun before November 19, 1986, if FDA is satisfied
that the data are scientifically valid and that the rights, safety, and

welfare of human subjects have not been violated.

\(d\) As sole basis for marketing approval. A PMA based solely on
foreign clinical data and otherwise meeting the criteria for approval
under this part may be approved if:

\(1\) The foreign data are applicable to the U.S. population and U.S.
medical practice;

\(2\) The studies have been performed by clinical investigators of
recognized competence; and

\(3\) The data may be considered valid without the need for an on-site
inspection by FDA or, if FDA considers such an inspection to be
necessary, FDA can validate the data through an on-site inspection or
other appropriate means.

\(e\) Consultation between FDA and applicants. Applicants are encouraged
to meet with FDA officials in a \`\`presubmission\'\' meeting when
approval based solely on foreign data will be sought.

Sec. 814.**17** Service of orders.

Orders issued under this part will be served in person by a designated
officer or employee of FDA on, or by registered mail to, the applicant
or the designated agent at the applicant\'s or designated agent\'s last
known address in FDA\'s records.

Sec. 814.**19** Product development protocol (PDP).

A class III device for which a product development protocol has been
declared completed by FDA under this chapter will be considered to have
an approved PMA.

**Subpart B\--Premarket Approval Application (PMA)**

Sec. 814.**20** Application.

\(a\) The applicant or an authorized representative shall sign the PMA.
If the applicant does not reside or have a place of business within the
United States, the PMA shall be countersigned by an authorized
representative residing or maintaining a place of business in the United
States and shall identify the representative\'s name and address.

\(b\) Unless the applicant justifies an omission in accordance with
paragraph (d) of this section, a PMA shall include:

\(1\) The name and address of the applicant.

\(2\) A table of contents that specifies the volume and page number for
each item referred to in the table. A PMA shall include separate
sections on nonclinical laboratory studies and on clinical

investigations involving human subjects. A PMA shall be submitted in six
copies each bound in one or more numbered volumes of reasonable size.
The applicant shall include information that it believes to be trade
secret or confidential commercial or financial information in all copies

of the PMA and identify in at least one copy the information that it
believes to be trade secret or confidential commercial or financial
information.

\(3\) A summary in sufficient detail that the reader may gain a general
understanding of the data and information in the application. The
summary shall contain the following information:

\(i\) Indications for use. A general description of the disease or
condition the device will diagnose, treat, prevent, cure, or mitigate,
including a description of the patient population for which the device
is intended.

\(ii\) Device description. An explanation of how the device functions,
the basic scientific concepts that form the basis for the device, and
the significant physical and performance characteristics of the device.
A brief description of the manufacturing process should be included if
it will significantly enhance the reader\'s understanding of the device.
The generic name of the device as well as any proprietary name or trade
name should be included.

\(iii\) Alternative practices and procedures. A description of existing
alternative practices or procedures for diagnosing, treating,
preventing, curing, or mitigating the disease or condition for which the
device is intended.

\(iv\) Marketing history. A brief description of the foreign and U.S.
marketing history, if any, of the device, including a list of all
countries in which the device has been marketed and a list of all

countries in which the device has been withdrawn from marketing for any
reason related to the safety or effectiveness of the device. The
description shall include the history of the marketing of the device by
the applicant and, if known, the history of the marketing of the device
by any other person.

\(v\) Summary of studies. An abstract of any information or report
described in the PMA under paragraph (b)(8)(ii) of this section and a
summary of the results of technical data submitted under paragraph
(b)(6) of this section. Such summary shall include a description of the

objective of the study, a description of the experimental design of the
study, a brief description of how the data were collected and analyzed,
and a brief description of the results, whether positive, negative, or
inconclusive. This section shall include the following:

\(A\) A summary of the nonclinical laboratory studies submitted in the
application;

\(B\) A summary of the clinical investigations involving human subjects
submitted in the application including a discussion of subject selection
and exclusion criteria, study population, study period, safety and
effectiveness data, adverse reactions and complications, patient

discontinuation, patient complaints, device failures and replacements,
results of statistical analyses of the clinical investigations,
contraindications and precautions for use of the device, and other
information from the clinical investigations as appropriate (any
investigation conducted under an IDE shall be identified as such).

\(vi\) Conclusions drawn from the studies. A discussion demonstrating
that the data and information in the application constitute valid
scientific evidence within the meaning of Sec. 860.7 and provide
reasonable assurance that the device is safe and effective for its
intended use. A concluding discussion shall present benefit and risk
considerations related to the device including a discussion of any
adverse effects of the device on health and any proposed additional

studies or surveillance the applicant intends to conduct following
approval of the PMA.

\(4\) A complete description of:

\(i\) The device, including pictorial representations;

\(ii\) Each of the functional components or ingredients of the device if
the device consists of more than one physical component or ingredient;

\(iii\) The properties of the device relevant to the diagnosis,
treatment, prevention, cure, or mitigation of a disease or condition;

\(iv\) The principles of operation of the device; and

\(v\) The methods used in, and the facilities and controls used for, the
manufacture, processing, packing, storage, and, where appropriate,
installation of the device, in sufficient detail so that a person
generally familiar with current good manufacturing practice can make a
knowledgeable judgment about the quality control used in the manufacture
of the device.

\(5\) Reference to any performance standard under section 514 of the act
or the Radiation Control for Health and Safety Act of 1968 (42 U.S.C.
263b et seq.) in effect or proposed at the time of the submission and to
any voluntary standard that is relevant to any aspect of the safety or
effectiveness of the device and that is known to or that should
reasonably be known to the applicant. The applicant shall\--

\(i\) Provide adequate information to demonstrate how the device meets,
or justify any deviation from, any performance standard established
under section 514 of the act or under the Radiation Control for Health
and Safety Act, and

\(ii\) Explain any deviation from a voluntary standard.

\(6\) The following technical sections which shall contain data and
information in sufficient detail to permit FDA to determine whether to
approve or deny approval of the application:

\(i\) A section containing results of the nonclinical laboratory studies
with the device including microbiological, toxicological, immunological,
biocompatibility, stress, wear, shelf life, and other laboratory or
animal tests as appropriate. Information on nonclinical laboratory
studies shall include a statement that each such study was conducted in
compliance with part 58, or, if the study was not conducted in
compliance with such regulations, a brief statement of the reason for
the noncompliance.

\(ii\) A section containing results of the clinical investigations
involving human subjects with the device including clinical protocols,
number of investigators and subjects per investigator, subject selection
and exclusion criteria, study population, study period, safety and

effectiveness data, adverse reactions and complications, patient
discontinuation, patient complaints, device failures and replacements,
tabulations of data from all individual subject report forms and copies
of such forms for each subject who died during a clinical investigation

or who did not complete the investigation, results of statistical
analyses of the clinical investigations, device failures and
replacements, contraindications and precautions for use of the device,
and any other appropriate information from the clinical investigations.
Any investigation conducted under an IDE shall be identified as such.
Information on clinical investigations involving human subjects shall
include the following:

\(A\) A statement with respect to each study that it either was
conducted in compliance with the institutional review board regulations
in part 56, or was not subject to the regulations under Sec. 56.104 or
Sec. 56.105, and that it was conducted in compliance with the informed
consent regulations in part 50; or if the study was not conducted in
compliance with those regulations, a brief statement of the reason for
the noncompliance.

\(B\) A statement that each study was conducted in compliance with part
812 or part 813 concerning sponsors of clinical investigations and
clinical investigators, or if the study was not conducted in compliance
with those regulations, a brief statement of the reason for the

noncompliance.

\(7\) For a PMA supported solely by data from one investigation, a
justification showing that data and other information from a single
investigator are sufficient to demonstrate the safety and effectiveness
of the device and to ensure reproducibility of test results.

(8)(i) A bibliography of all published reports not submitted under
paragraph (b)(6) of this section, whether adverse or supportive, known
to or that should reasonably be known to the applicant and that concern
the safety or effectiveness of the device.

\(ii\) An identification, discussion, and analysis of any other data,
information, or report relevant to an evaluation of the safety and
effectiveness of the device known to or that should reasonably be known
to the applicant from any source, foreign or domestic, including

information derived from investigations other than those proposed in the
application and from commercial marketing experience.

\(iii\) Copies of such published reports or unpublished information in
the possession of or reasonably obtainable by the applicant if an FDA
advisory committee or FDA requests.

\(9\) One or more samples of the device and its components, if requested
by FDA. If it is impractical to submit a requested sample of the device,
the applicant shall name the location at which FDA may examine and test
one or more devices.

\(10\) Copies of all proposed labeling for the device. Such labeling may
include, e.g., instructions for installation and any information,
literature, or advertising that constitutes labeling under section
201(m) of the act.

\(11\) An environmental assessment under Sec. 25.**20**(n) prepared in
the applicable format in Sec. 25.40, unless the action qualifies for
exclusion under Sec. 25.30 or Sec. 25.34. If the applicant believes that
the action qualifies for exclusion, the PMA shall under Sec. 25.15(a)

and (d) provide information that establishes to FDA\'s satisfaction that
the action requested is included within the excluded category and meets
the criteria for the applicable exclusion.

\(12\) A financial certification or disclosure statement or both as
required by part 54 of this chapter.

\(13\) Such other information as FDA may request. If necessary, FDA will
obtain the concurrence of the appropriate FDA advisory committee before
requesting additional information.

\(c\) Pertinent information in FDA files specifically referred to by an
applicant may be incorporated into a PMA by reference. Information in a
master file or other information submitted to FDA by a person other than
the applicant will not be considered part of a PMA unless such reference
is authorized in writing by the person who submitted the information or
the master file. If a master file is not referenced within 5 years after
the date that it is submitted to FDA, FDA will return the master file to
the person who submitted it.

\(d\) If the applicant believes that certain information required under
paragraph (b) of this section to be in a PMA is not applicable to the
device that is the subject of the PMA, and omits any such information
from its PMA, the applicant shall submit a statement that identifies the
omitted information and justifies the omission. The statement shall be
submitted as a separate section in the PMA and identified in the table
of contents. If the justification for the omission is not accepted by
the agency, FDA will so notify the applicant.

\(e\) The applicant shall periodically update its pending application
with new safety and effectiveness information learned about the device
from ongoing or completed studies that may reasonably affect an
evaluation of the safety or effectiveness of the device or that may

reasonably affect the statement of contraindications, warnings,
precautions, and adverse reactions in the draft labeling. The update
report shall be consistent with the data reporting provisions of the
protocol. The applicant shall submit three copies of any update report

and shall include in the report the number assigned by FDA to the PMA.
These updates are considered to be amendments to the PMA. The time frame
for review of a PMA will not be extended due to the submission of an
update report unless the update is a major amendment under Sec.
814.37(c)(1). The applicant shall submit these reports\--

\(1\) 3 months after the filing date,

\(2\) Following receipt of an approvable letter, and

\(3\) At any other time as requested by FDA.

\(f\) If a color additive subject to section 706 of the act is used in
or on the device and has not previously been listed for such use, then,
in lieu of submitting a color additive petition under part 71, at the
option of the applicant, the information required to be submitted under
part 71 may be submitted as part of the PMA. When submitted as part of
the PMA, the information shall be submitted in three copies each bound
in one or more numbered volumes of reasonable size. A PMA for a device
that contains a color additive that is subject to section 706 of the act
will not be approved until the color additive is listed for use in or on
the device.

\(g\) FDA has issued a PMA guidance document to assist the applicant in
the arrangement and content of a PMA. This guidance document is
available on the Internet at
http://www.fda.gov/cdrh/dsma/pmaman/front.html. This guidance document
is also available upon request from the Center for Devices and
Radiological Health, Division of Small Manufacturers Assistance
(HFZ-220), 1350 Piccard Dr., Rockville, MD 20850, FAX 301-443-8818.

\(h\) If you are sending a PMA, PMA amendment, PMA supplement, or
correspondence with respect to a PMA, you must send it to the Document
Mail Center (HFZ-401), Center for Devices and Radiological Health, Food
and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850.

Sec. 814.**37** PMA amendments and resubmitted PMA\'s.

\(a\) An applicant may amend a pending PMA or PMA supplement to revise
existing information or provide additional information.

\(b\) FDA may request the applicant to amend a PMA or PMA supplement
with any information regarding the device that is necessary for FDA or
the appropriate advisory committee to complete the review of the PMA or
PMA supplement.

\(c\) A PMA amendment submitted to FDA shall include the PMA or PMA
supplement number assigned to the original submission and, if submitted
on the applicant\'s own initiative, the reason for submitting the
amendment. FDA may extend the time required for its review of the PMA,

or PMA supplement, as follows:

\(1\) If the applicant on its own initiative or at FDA\'s request
submits a major PMA amendment (e.g., an amendment that contains
significant new data from a previously unreported study, significant
updated data from a previously reported study, detailed new analyses of
previously submitted data, or significant required information
previously omitted), the review period may be extended up to 180 days.

\(2\) If an applicant declines to submit a major amendment requested by
FDA, the review period may be extended for the number of days that
elapse between the date of such request and the date that FDA receives
the written response declining to submit the requested amendment.

\(d\) An applicant may on its own initiative withdraw a PMA or PMA
supplement. If FDA requests an applicant to submit a PMA amendment and a
written response to FDA\'s request is not received within 180 days of
the date of the request, FDA will consider the pending PMA or PMA
supplement to be withdrawn voluntarily by the applicant.

\(e\) An applicant may resubmit a PMA or PMA supplement after
withdrawing it or after it is considered withdrawn under paragraph (d)
of this section, or after FDA has refused to accept it for filing, or
has denied approval of the PMA or PMA supplement. A resubmitted PMA or
PMA supplement shall comply with the requirements of Sec. 814.20 or Sec.
814.39, respectively, and shall include the PMA number assigned to the
original submission and the applicant\'s reasons for resubmission of the
PMA or PMA supplement.

Sec. 814.**39** PMA supplements.

\(a\) After FDA\'s approval of a PMA, an applicant shall submit a PMA
supplement for review and approval by FDA before making a change
affecting the safety or effectiveness of the device for which the
applicant has an approved PMA, unless the change is of a type for which
FDA, under paragraph (e) of this section, has advised that an alternate
submission is permitted or is of a type which, under section
515(d)(6)(A) of the act and paragraph (f) of this section, does not

require a PMA supplement under this paragraph. While the burden for
determining whether a supplement is required is primarily on the PMA
holder, changes for which an applicant shall submit a PMA supplement
include, but are not limited to, the following types of changes if they

affect the safety or effectiveness of the device:

\(1\) New indications for use of the device.

\(2\) Labeling changes.

\(3\) The use of a different facility or establishment to manufacture,
process, or package the device.

\(4\) Changes in sterilization procedures.

\(5\) Changes in packaging.

\(6\) Changes in the performance or design specifications, circuits,
components, ingredients, principle of operation, or physical layout of
the device.

\(7\) Extension of the expiration date of the device based on data
obtained under a new or revised stability or sterility testing protocol
that has not been approved by FDA. If the protocol has been approved,
the change shall be reported to FDA under paragraph (b) of this section.

\(b\) An applicant may make a change in a device after FDA\'s approval
of a PMA for the device without submitting a PMA supplement if the
change does not affect the device\'s safety or effectiveness and the
change is reported to FDA in postapproval periodic reports required as a

condition to approval of the device, e.g., an editorial change in
labeling which does not affect the safety or effectiveness of the
device.

\(c\) All procedures and actions that apply to an application under Sec.
814.20 also apply to PMA supplements except that the information
required in a supplement is limited to that needed to support the
change. A summary under Sec. 814.20(b)(3) is required for only a
supplement submitted for new indications for use of the device,
significant changes in the performance or design specifications,
circuits, components, ingredients, principles of operation, or physical

layout of the device, or when otherwise required by FDA. The applicant
shall submit three copies of a PMA supplement and shall include
information relevant to the proposed changes in the device. A PMA
supplement shall include a separate section that identifies each change
for which approval is being requested and explains the reason for each
such change. The applicant shall submit additional copies and additional
information if requested by FDA. The time frames for review of, and FDA
action on, a PMA supplement are the same as those provided in Sec.
814.40 for a PMA.

(d)(1) After FDA approves a PMA, any change described in paragraph
(d)(2) of this section that enhances the safety of the device or the
safety in the use of the device may be placed into effect by the
applicant prior to the receipt under Sec. 814.17 of a written FDA order
approving the PMA supplement provided that:

\(i\) The PMA supplement and its mailing cover are plainly marked
\`\`Special PMA Supplement\--Changes Being Effected\'\';

\(ii\) The PMA supplement provides a full explanation of the basis for
the changes;

\(iii\) The applicant has received acknowledgement from FDA of receipt
of the supplement; and

\(iv\) The PMA supplement specifically identifies the date that such
changes are being effected.

\(2\) The following changes are permitted by paragraph (d)(1) of this
section:

\(i\) Labeling changes that add or strengthen a contraindication,
warning, precaution, or information about an adverse reaction.

\(ii\) Labeling changes that add or strengthen an instruction that is
intended to enhance the safe use of the device.

\(iii\) Labeling changes that delete misleading, false, or unsupported
indications.

\(iv\) Changes in quality controls or manufacturing process that add a
new specification or test method, or otherwise provide additional
assurance of purity, identity, strength, or reliability of the device.

\(e\) FDA will identify a change to a device for which an applicant has
an approved PMA and for which a PMA supplement under paragraph (a) is
not required. FDA will identify such a change in an advisory opinion
under Sec. 10.85, if the change applies to a generic type of device, or
in correspondence to the applicant, if the change applies only to the
applicant\'s device. FDA will require that a change for which a PMA
supplement under paragraph (a) is not required be reported to FDA in\--

\(1\) A periodic report under Sec. 814.84 or

\(2\) A 30-day PMA supplement under this paragraph.

\(f\) Under section 515(d) of the act, modifications to manufacturing
procedures or methods of manufacture that affect the safety and
effectiveness of a device subject to an approved PMA do not require
submission of a PMA supplement under paragraph (a) of this section and
are eligible to be the subject of a 30-day notice. A 30-day notice shall
describe in detail the change, summarize the data or information
supporting the change, and state that the change has been made in
accordance with the requirements of part 820 of this chapter. The
manufacturer may distribute the device 30 days after the date on which
FDA receives the 30-day notice, unless FDA notifies the applicant within
30 days from receipt of the notice that the notice is not adequate. If
the notice is not adequate, FDA shall inform the applicant in writing
that a 135-day PMA supplement is needed and shall describe what further
information or action is required for acceptance of such change. The
number of days under review as a 30-day notice shall be deducted from
the 135-day PMA supplement review period if the notice meets appropriate

content requirements for a PMA supplement. FDA will identify, in the
advisory opinion or correspondence, the type of information that is to
be included in the report or 30-day PMA

supplement. lf the change is required to be reported to FDA in a
periodic report, the change may be made before it is reported to FDA. If
the change is required to be reported in a 30-day PMA supplement, the
change may be made 30 days after FDA files the 30-day PMA supplement

unless FDA requires the PMA holder to provide additional information,
informs the PMA holder that the supplement is not approvable, or
disapproves the supplement. The 30-day PMA supplement shall follow the
instructions in the correspondence or advisory opinion. Any 30-day PMA
supplement that does not meet the requirements of the correspondence or
advisory opinion will not be filed and, therefore, will not be deemed
approved 30 days after receipt.

**Subpart C\--FDA Action on a PMA**

Sec. 814.**40** Time frames for reviewing a PMA.

Within 180 days after receipt of an application that is accepted for
filing and to which the applicant does not submit a major amendment, FDA
will review the PMA and, after receiving the report and recommendation
of the appropriate FDA advisory committee, send the applicant an
approval order under Sec. 814.44(d), an approvable letter under Sec.
814.44(e), a not approvable letter under Sec. 814.44(f), or an order
denying approval under Sec. 814.45. The approvable letter and the not
approvable letter will provide an opportunity for the applicant to

amend or withdraw the application, or to consider the letter to be a
denial of approval of the PMA under Sec. 814.45 and to request
administrative review under section 515 (d)(3) and (g) of the act.

Sec. 814.**42** Filing a PMA.

\(a\) The filing of an application means that FDA has made a threshold
determination that the application is sufficiently complete to permit a
substantive review. Within 45 days after a PMA is received by FDA, the
agency will notify the applicant whether the application has been filed.

\(b\) If FDA does not find that any of the reasons in paragraph (e) of
this section for refusing to file the PMA applies, the agency will file
the PMA and will notify the applicant in writing of the filing. The
notice will include the PMA reference number and the date FDA filed the
PMA. The date of filing is the date that a PMA accepted for filing was
received by the agency. The 180-day period for review of a PMA starts on
the date of filing.

\(c\) If FDA refuses to file a PMA, the agency will notify the applicant
of the reasons for the refusal. This notice will identify the
deficiencies in the application that prevent filing and will include the
PMA reference number.

\(d\) If FDA refuses to file the PMA, the applicant may:

\(1\) Resubmit the PMA with additional information necessary to comply
with the requirements of section 515(c)(1) (A)-(G) of the act and Sec.
814.20. A resubmitted PMA shall include the PMA reference number of the
original submission. If the resubmitted PMA is accepted for filing,

the date of filing is the date FDA receives the resubmission;

\(2\) Request in writing within 10 working days of the date of receipt
of the notice refusing to file the PMA, an informal conference with the
Director of the Office of Device Evaluation to review FDA\'s decision
not to file the PMA. FDA will hold the informal conference within 10
working days of its receipt of the request and will render its decision
on filing within 5 working days after the informal conference. If, after
the informal conference, FDA accepts the PMA for filing, the date of
filing will be the date of the decision to accept the PMA for filing. If
FDA does not reverse its decision not to file the PMA, the applicant may
request reconsideration of the decision from the Director of the Center
for Devices and Radiological Health. The Director\'s decision will
constitute final administrative action for the purpose of judicial
review.

\(e\) FDA may refuse to file a PMA if any of the following applies:

\(1\) The application is incomplete because it does not on its face
contain all the information required under section 515(c)(1) (A)-(G) of
the act;

\(2\) The PMA does not contain each of the items required under Sec.
814.20 and justification for omission of any item is inadequate;

\(3\) The applicant has a pending premarket notification under section
510(k) of the act with respect to the same device, and FDA has not
determined whether the device falls within the scope of Sec. 814.1(c).

\(4\) The PMA contains a false statement of material fact.

\(5\) The PMA is not accompanied by a statement of either certification
or disclosure as required by part 54 of this chapter.

Sec. 814.**44** Procedures for review of a PMA.

\(a\) FDA will begin substantive review of a PMA after the PMA is
accepted for filing under Sec. 814.42. FDA may refer the PMA to a panel
on its own initiative, and will do so upon request of an applicant,
unless FDA determines that the application substantially duplicates

information previously reviewed by a panel. If FDA refers an application
to a panel, FDA will forward the PMA, or relevant portions thereof, to
each member of the appropriate FDA panel for review. During the review
process, FDA may communicate with the applicant as set forth under

Sec. 814.37(b), or with a panel to respond to questions that may be
posed by panel members or to provide additional information to the
panel. FDA will maintain a record of all communications with the
applicant and with the panel.

\(b\) The advisory committee shall submit a report to FDA which includes
the committee\'s recommendation and the basis for such recommendation on
the PMA. Before submission of this report, the committee shall hold a
public meeting to review the PMA in accordance with part 14. This
meeting may be held by a telephone conference under Sec. 14.22(g). The
advisory committee report and recommendation may be in the form of a
meeting transcript signed by the chairperson of the committee.

\(c\) FDA will complete its review of the PMA and the advisory committee
report and recommendation and, within the later of 180 days from the
date of filing of the PMA under Sec. 814.42 or the number of days after
the date of filing as determined under Sec. 814.37(c), issue

an approval order under paragraph (d) of this section, an approvable
letter under paragraph (e) of this section, a not approvable letter
under paragraph (f) of this section, or an order denying approval of the
application under Sec. 814.45(a).

(d)(1) FDA will issue to the applicant an order approving a PMA if none
of the reasons in Sec. 814.45 for denying approval of the application
applies. FDA will approve an application on the basis of draft final
labeling if the only deficiencies in the application concern editorial
or similar minor deficiencies in the draft final labeling. Such approval
will be conditioned upon the applicant incorporating the specified
labeling changes exactly as directed and upon the applicant submitting
to FDA a copy of the final printed labeling before marketing. FDA will
also give the public notice of the order, including notice of and
opportunity for any interested persons to request review under section
515(d)(3) of the act. The notice of approval will be placed on FDA\'s
home page on the Internet (http://www.fda.gov), and it will state that a
detailed summary of information respecting the safety and effectiveness
of the device, which was the basis for the order approving the PMA,
including information about any adverse effects of the device on health,
is available on the Internet and has been placed on public display, and
that copies are available upon request. FDA will publish in the Federal
Register after each quarter a list of the approvals announced in that
quarter. When a notice of approval is published, data and information in
the PMA file will be available for public disclosure in accordance with

Sec. 814.9.

\(2\) A request for copies of the current PMA approvals and denials
document and for copies of summaries of safety and effectiveness shall
be sent in writing to the Dockets Management Branch (HFA-305), Food and
Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

\(e\) FDA will send the applicant an approvable letter if the
application substantially meets the requirements of this part and the
agency believes it can approve the application if specific additional
information is submitted or specific conditions are agreed to by the
applicant.

\(1\) The approvable letter will describe the information FDA requires
to be provided by the applicant or the conditions the applicant is
required to meet to obtain approval. For example, FDA may require, as a
condition to approval:

\(i\) The submission of certain information identified in the approvable
letter, e.g., final labeling;

\(ii\) An FDA inspection that finds the manufacturing facilities,
methods, and controls in compliance with part 820 and, if applicable,
that verifies records pertinent to the PMA;

\(iii\) Restrictions imposed on the device under section
515(d)(1)(B)(ii) or 520(e) of the act;

\(iv\) Postapproval requirements as described in subpart E of this part.

\(2\) In response to an approvable letter the applicant may:

\(i\) Amend the PMA as requested in the approvable letter; or

\(ii\) Consider the approvable letter to be a denial of approval of the
PMA under Sec. 814.45 and request administrative review under section
515(d)(3) of the act by filing a petition in the form of a petition for
reconsideration under Sec. 10.33; or

\(iii\) Withdraw the PMA.

\(f\) FDA will send the applicant a not approvable letter if the agency
believes that the application may not be approved for one or more of the
reasons given in Sec. 814.45(a). The not approvable letter will describe
the deficiencies in the application, including each applicable

ground for denial under section 515(d)(2) (A)-(E) of the act, and, where
practical, will identify measures required to place the PMA in
approvable form. In response to a not approvable letter, the applicant
may:

\(1\) Amend the PMA as requested in the not approvable letter (such an
amendment will be considered a major amendment under Sec. 814.37(c)(1));
or

\(2\) Consider the not approvable letter to be a denial of approval of
the PMA under Sec. 814.45 and request administrative review under
section 515(d)(3) of the act by filing a petition in the form of a
petition for reconsideration under Sec. 10.33; or

\(3\) Withdraw the PMA.

\(g\) FDA will consider a PMA to have been withdrawn voluntarily if:

\(1\) The applicant fails to respond in writing to a written request for
an amendment within 180 days after the date FDA issues such request;

\(2\) The applicant fails to respond in writing to an approvable or not
approvable letter within 180 days after the date FDA issues such letter;
or

\(3\) The applicant submits a written notice to FDA that the PMA has
been withdrawn.

Sec. 814.**45** Denial of approval of a PMA.

\(a\) FDA may issue an order denying approval of a PMA if the applicant
fails to follow the requirements of this part or if, upon the basis of
the information submitted in the PMA or any other information before the
agency, FDA determines that any of the grounds for denying

approval of a PMA specified in section 515(d)(2) (A)-(E) of the act
applies. In addition, FDA may deny approval of a PMA for any of the
following reasons:

\(1\) The PMA contains a false statement of material fact;

\(2\) The device\'s proposed labeling does not comply with the
requirements in part 801 or part 809;

\(3\) The applicant does not permit an authorized FDA employee an
opportunity to inspect at a reasonable time and in a reasonable manner
the facilities, controls, and to have access to and to copy and verify
all records pertinent to the application;

\(4\) A nonclinical laboratory study that is described in the PMA and
that is essential to show that the device is safe for use under the
conditions prescribed, recommended, or suggested in its proposed
labeling, was not conducted in compliance with the good laboratory
practice regulations in part 58 and no reason for the noncompliance is
provided or, if it is, the differences between the practices used in
conducting the study and the good laboratory practice regulations do not
support the validity of the study; or

\(5\) Any clinical investigation involving human subjects described in
the PMA, subject to the institutional review board regulations in part
56 or informed consent regulations in part 50, was not conducted in
compliance with those regulations such that the rights or safety of
human subjects were not adequately protected.

\(b\) FDA will issue any order denying approval of the PMA in accordance
with Sec. 814.17. The order will inform the applicant of the
deficiencies in the PMA, including each applicable ground for denial
under section 515(d)(2) of the act and the regulations under this part,
and, where practical, will identify measures required to place the PMA
in approvable form. The order will include a notice of an opportunity to
request review under section 515(d)(3) of the act.

\(c\) FDA will use the criteria specified in Sec. 860.7 to determine the
safety and effectiveness of a device in deciding whether to approve or
deny approval of a PMA. FDA may use information other than that
submitted by the applicant in making such determination.

(d)(1) FDA will give the public notice of an order denying approval of
the PMA. The notice will be placed on the FDA\'s home page on the
Internet (http://www.fda.gov), and it will state that a detailed summary
of information respecting the safety and effectiveness of the device,
ncluding information about any adverse effects of the device on health,
is available on the Internet and has been placed on public display and
that copies are available upon request. FDA will publish in the Federal
Register after each quarter a list of the denials announced in that
quarter. When a notice of denial of approval is made publicly available,
data and information in the PMA file will be available for public
disclosure in accordance with Sec. 814.9.

\(2\) A request for copies of the current PMA approvals and denials
document and copies of summaries of safety and effectiveness shall be
sent in writing to the Freedom of Information Staff (HFI-35), Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

\(e\) FDA will issue an order denying approval of a PMA after an
approvable or not approvable letter has been sent and the applicant:

\(1\) Submits a requested amendment but any ground for denying approval
of the application under section 515(d)(2) of the act still applies; or

\(2\) Notifies FDA in writing that the requested amendment will not be
submitted; or

\(3\) Petitions for review under section 515(d)(3) of the act by filing
a petition in the form of a petition for reconsideration under Sec.
10.33.

Sec. 814.**46** Withdrawal of approval of a PMA.

\(a\) FDA may issue an order withdrawing approval of a PMA if, from any
information available to the agency, FDA determines that:

\(1\) Any of the grounds under section 515(e)(1) (A)-(G) of the act
applies.

\(2\) Any postapproval requirement imposed by the PMA approval order or
by regulation has not been met.

\(3\) A nonclinical laboratory study that is described in the PMA and
that is essential to show that the device is safe for use under the
conditions prescribed, recommended, or suggested in its proposed
labeling, was not conducted in compliance with the good laboratory
practice regulations in part 58 and no reason for the noncompliance is
provided or, if it is, the differences between the practices used in
conducting the study and the good laboratory practice regulations do not
support the validity of the study.

\(4\) Any clinical investigation involving human subjects described in
the PMA, subject to the institutional review board regulations in part
56 or informed consent regulations in part 50, was not conducted in
compliance with those regulations such that the rights or safety of
human subjects were not adequately protected.

(b)(1) FDA may seek advice on scientific matters from any appropriate
FDA advisory committee in deciding whether to withdraw approval of a
PMA.

\(2\) FDA may use information other than that submitted by the applicant
in deciding whether to withdraw approval of a PMA.

\(c\) Before issuing an order withdrawing approval of a PMA, FDA will
issue the holder of the approved application a notice of opportunity for
an informal hearing under part 16.

\(d\) If the applicant does not request a hearing or if after the part
16 hearing is held the agency decides to proceed with the withdrawal,
FDA will issue to the holder of the approved application an order
withdrawing approval of the application. The order will be issued under
Sec. 814.17, will state each ground for withdrawing approval, and will
include a notice of an opportunity for administrative review under
section 515(e)(2) of the act.

\(e\) FDA will give the public notice of an order withdrawing approval
of a PMA. The notice will be published in the Federal Register and will
state that a detailed summary of information respecting the safety and
effectiveness of the device, including information about any adverse

effects of the device on health, has been placed on public display and
that copies are available upon request. When a notice of withdrawal of
approval is published, data and information in the PMA file will be
available for public disclosure in accordance with Sec. 814.9.

Sec. 814.**47** Temporary suspension of approval of a PMA.

\(a\) Scope. (1) This section describes the procedures that FDA will
follow in exercising its authority under section 515(e)(3) of the act
(21 U.S.C. 360e(e)(3)). This authority applies to the original PMA, as
well as any PMA supplement(s), for a medical device.

\(2\) FDA will issue an order temporarily suspending approval of a PMA
if FDA determines that there is a reasonable probability that continued
distribution of the device would cause serious, adverse health
consequences or death.

\(b\) Regulatory hearing. (1) If FDA believes that there is a reasonable
probability that the continued distribution of a device subject to an
approved PMA would cause serious, adverse health consequences or death,
FDA may initiate and conduct a regulatory hearing to determine whether
to issue an order temporarily suspending approval of the PMA.

\(2\) Any regulatory hearing to determine whether to issue an order
temporarily suspending approval of a PMA shall be initiated and
conducted by FDA pursuant to part 16 of this chapter. If FDA believes
that immediate action to remove a dangerous device from the market is

necessary to protect the public health, the agency may, in accordance
with Sec. 16.60(h) of this

chapter, waive, suspend, or modify any part 16 procedure pursuant to
Sec. 10.19 of this chapter.

\(3\) FDA shall deem the PMA holder\'s failure to request a hearing
within the timeframe specified by FDA in the notice of opportunity for
hearing to be a waiver.

\(c\) Temporary suspension order. If the PMA holder does not request a
regulatory hearing or if, after the hearing, and after consideration of
the administrative record of the hearing, FDA determines that there is a
reasonable probability that the continued distribution of a device under

an approved PMA would cause serious, adverse health consequences or
death, the agency shall, under the authority of section 515(e)(3) of the
act, issue an order to the PMA holder temporarily suspending approval of
the PMA.

\(d\) Permanent withdrawal of approval of the PMA. If FDA issues an
order temporarily suspending approval of a PMA, the agency shall proceed
expeditiously, but within 60 days, to hold a hearing on whether to
permanently withdraw approval of the PMA in accordance with section
515(e)(1) of the act and the procedures set out in Sec. 814.46.

**Subpart D\--Administrative Review \[Reserved\]**

**Subpart E\--Postapproval Requirements**

Sec. 814.**80** General.

A device may not be manufactured, packaged, stored, labeled,
distributed, or advertised in a manner that is inconsistent with any
conditions to approval specified in the PMA approval order for the
device.

Sec. 814.**82** Postapproval requirements.

\(a\) FDA may impose postapproval requirements in a PMA approval order
or by regulation at the time of approval of the PMA or by regulation
subsequent to approval. Postapproval requirements may include as a
condition to approval of the device:

\(1\) Restriction of the sale, distribution, or use of the device as
provided by section 515(d)(1)(B)(ii) or 520(e) of the act.

\(2\) Continuing evaluation and periodic reporting on the safety,
effectiveness, and reliability of the device for its intended use. FDA
will state in the PMA approval order the reason or purpose for such
requirement and the number of patients to be evaluated and the reports
required to be submitted.

\(3\) Prominent display in the labeling of a device and in the
advertising of any restricted device of warnings, hazards, or
precautions important for the device\'s safe and effective use,
including

patient information, e.g., information provided to the patient on
alternative modes of therapy and on risks and benefits associated with
the use of the device.

\(4\) Inclusion of identification codes on the device or its labeling,
or in the case of an implant, on cards given to patients if necessary to
protect the public health.

\(5\) Maintenance of records that will enable the applicant to submit to
FDA information needed to trace patients if such information is
necessary to protect the public health. Under section 519(a)(4) of the
act, FDA will require that the identity of any patient be disclosed in
records maintained under this paragraph only to the extent required for
the medical welfare of the individual, to determine the safety or
effectiveness of the device, or to verify a record, report, or

information submitted to the agency.

\(6\) Maintenance of records for specified periods of time and
organization and indexing of records into identifiable files to enable
FDA to determine whether there is reasonable assurance of the continued
safety and effectiveness of the device.

\(7\) Submission to FDA at intervals specified in the approval order of
periodic reports containing the information required by Sec. 814.84(b).

\(8\) Batch testing of the device.

\(9\) Such other requirements as FDA determines are necessary to provide
reasonable assurance, or continued reasonable assurance, of the safety
and effectiveness of the device.

\(b\) An applicant shall grant to FDA access to any records and reports
required under the provisions of this part, and shall permit authorized
FDA employees to copy and verify such records and reports and to inspect
at a reasonable time and in a reasonable manner all

manufacturing facilities to verify that the device is being
manufactured, stored, labeled, and shipped under approved conditions.

\(c\) Failure to comply with any postapproval requirement constitutes a
ground for withdrawal of approval of a PMA.

Sec. 814.**84** Reports.

\(a\) The holder of an approved PMA shall comply with the requirements
of part 803 and with any other requirements applicable to the device by
other regulations in this subchapter or by order approving the device.

\(b\) Unless FDA specifies otherwise, any periodic report shall:

\(1\) Identify changes described in Sec. 814.39(a) and changes required
to be reported to FDA under Sec. 814.39(b).

\(2\) Contain a summary and bibliography of the following information
not previously submitted as part of the PMA:

\(i\) Unpublished reports of data from any clinical investigations or
nonclinical laboratory studies involving the device or related devices
and known to or that reasonably should be known to the applicant.

\(ii\) Reports in the scientific literature concerning the device and
known to or that reasonably should be known to the applicant. If, after
reviewing the summary and bibliography, FDA concludes that the agency
needs a copy of the unpublished or published reports, FDA will notify

the applicant that copies of such reports shall be submitted.

**Subparts F-G \[Reserved\]**

**Subpart H\--Humanitarian Use Devices**

Sec. 814.**100** Purpose and scope.

\(a\) This subpart H implements section 520(m) of the act. The purpose
of section 520(m) is, to the extent consistent with the protection of
the public health and safety and with ethical standards, to encourage
the discovery and use of devices intended to benefit patients in the

treatment or diagnosis of diseases or conditions that affect or are
manifested in fewer than 4,000 individuals in the United States per
year. This subpart provides procedures for obtaining:

\(1\) HUD designation of a medical device; and

\(2\) Marketing approval for the HUD notwithstanding the absence of
reasonable assurance of effectiveness that would otherwise be required
under sections 514 and 515 of the act.

\(b\) Although a HUD may also have uses that differ from the
humanitarian use, applicants seeking approval of any non-HUD use shall
submit a PMA as required under Sec. 814.20, or a premarket notification
as required under part 807 of this chapter.

\(c\) Obtaining marketing approval for a HUD involves two steps:

\(1\) Obtaining designation of the device as a HUD from FDA\'s Office of
Orphan Products Development, and

\(2\) Submitting an HDE to the Office of Device Evaluation (ODE), Center
for Devices and Radiological Health (CDRH).

\(d\) A person granted an exemption under section 520(m) of the act
shall submit periodic reports as described in Sec. 814.126(b).

\(e\) FDA may suspend or withdraw approval of an HDE after providing
notice and an opportunity for an informal hearing.

Sec. 814.**102** Designation of HUD status.

\(a\) Request for designation. Prior to submitting an HDE application,
the applicant shall submit a request for HUD designation to FDA\'s
Office of Orphan Products Development. The request

shall contain the following:

\(1\) A statement that the applicant requests HUD designation for a rare
disease or condition or a valid subset of a disease or condition which
shall be identified with specificity;

\(2\) The name and address of the applicant, the name of the
applicant\'s primary contact person and/or resident agent, including
title, address, and telephone number;

\(3\) A description of the rare disease or condition for which the
device is to be used, the proposed indication or indications for use of
the device, and the reasons why such therapy is needed. If the device is
proposed for an indication that represents a subset of a common disease

or condition, a demonstration that the subset is medically plausible
should be included;

\(4\) A description of the device and a discussion of the scientific
rationale for the use of the device for the rare disease or condition;
and

\(5\) Documentation, with appended authoritative references, to
demonstrate that the device is designed to treat or diagnose a disease
or condition that affects or is manifested in fewer than 4,000 people in
the United States per year. If the device is for diagnostic purposes,
the documentation must demonstrate that fewer than 4,000 patients per
year would be subjected to diagnosis by the device in the United States.
Authoritative references include literature citations in specialized
medical journals, textbooks, specialized medical society proceedings, or

governmental statistics publications. When no such studies or literature
citations exist, the applicant may be able to demonstrate the prevalence
of the disease or condition in the United States by providing credible
conclusions from appropriate research or surveys.

\(b\) FDA action. Within 45 days of receipt of a request for HUD
designation, FDA will take one of the following actions:

\(1\) Approve the request and notify the applicant that the device has
been designated as a HUD based on the information submitted;

\(2\) Return the request to the applicant pending further review upon
submission of additional information. This action will ensue if the
request is incomplete because it does not on its face contain all of the
information required under Sec. 814.**102**(a). Upon receipt of this
additional information, the review period may be extended up to 45 days;
or

\(3\) Disapprove the request for HUD designation based on a substantive
review of the information submitted. FDA may disapprove a request for
HUD designation if:

\(i\) There is insufficient evidence to support the estimate that the
disease or condition for which the device is designed to treat or
diagnose affects or is manifested in fewer than 4,000 people in the
United States per year;

\(ii\) FDA determines that, for a diagnostic device, 4,000 or more
patients in the United States would be subjected to diagnosis using the
device per year; or

\(iii\) FDA determines that the patient population defined in the
request is not a medically plausible subset of a larger population.

\(c\) Revocation of designation. FDA may revoke a HUD designation if the
agency finds that:

\(1\) The request for designation contained an untrue statement of
material fact or omitted material information; or

\(2\) Based on the evidence available, the device is not eligible for
HUD designation.

\(d\) Submission. The applicant shall submit two copies of a completed,
dated, and signed request for HUD designation to: Office of Orphan
Products Development (HF-35), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857.

Sec. 814.**104** Original applications.

\(a\) United States applicant or representative. The applicant or an
authorized representative shall sign the HDE. If the applicant does not
reside or have a place of business within the United States, the HDE
shall be countersigned by an authorized representative residing or
maintaining a place of business in the United States and shall identify
the representative\'s name and address.

\(b\) Contents. Unless the applicant justifies an omission in accordance
with paragraph (d) of this section, an HDE shall include:

\(1\) A copy of or reference to the determination made by FDA\'s Office
of Orphan Products Development (in accordance with Sec. 814.102) that
the device qualifies as a HUD;

\(2\) An explanation of why the device would not be available unless an
HDE were granted and a statement that no comparable device (other than
another HUD approved under this subpart or a device under an approved
IDE) is available to treat or diagnose the disease or condition. The
application also shall contain a discussion of the risks and benefits of
currently available devices or alternative forms of treatment in the
United States;

\(3\) An explanation of why the probable benefit to health from the use
of the device outweighs the risk of injury or illness from its use,
taking into account the probable risks and benefits of currently
available devices or alternative forms of treatment. Such explanation
shall include a description, explanation, or theory of the underlying
disease process or condition, and known or postulated mechanism(s) of
action of the device in relation to the disease process or condition;

\(4\) All of the information required to be submitted under Sec.
814.20(b), except that:

\(i\) In lieu of the summaries, conclusions, and results from clinical
investigations required under Secs. 814.20(b)(3)(v)(B), (b)(3)(vi), and
(b)(6)(ii), the applicant shall include the summaries, conclusions, and
results of all clinical experience or investigations (whether adverse or
supportive) reasonably obtainable by the applicant that are relevant to
an assessment of the risks and probable benefits of the device; and

\(ii\) In addition to the proposed labeling requirement set forth in
Sec. 814.20(b)(10), the labeling shall bear the following statement:
Humanitarian Device. Authorized by Federal law for use in the
\[treatment or diagnosis\] of \[specify disease or condition\]. The
effectiveness of this device for this use has not been demonstrated; and

\(5\) The amount to be charged for the device and, if the amount is more
than \$250, a report by an independent certified public accountant, made
in accordance with the Statement on Standards for Attestation
established by the American Institute of Certified Public Accountants,
or in lieu of such a report, an attestation by a responsible individual
of the organization, verifying that the amount charged does not exceed
the costs of the device\'s research, development, fabrication, and

distribution. If the amount charged is \$250 or less, the requirement
for a report by an ndependent certified public accountant or an
attestation by a responsible individual of the organization is waived.

\(c\) Omission of information. If the applicant believes that certain
information required under paragraph (b) of this section is not
applicable to the device that is the subject of the HDE, and omits any
such information from its HDE, the applicant shall submit a statement
that identifies and justifies the omission. The statement shall be
submitted as a separate section in the HDE and identified in the table
of contents. If the justification for the omission is not accepted by
the agency, FDA will so notify the applicant.

\(d\) Address for submissions and correspondence. Copies of all original
HDE\'s, amendments and supplements, as well as any correspondence
relating to an HDE, shall be sent or delivered to the Document Mail
Center (HFZ-401), Office of Device Evaluation, Center for Devices and
Radiological Health, Food and Drug Administration, 9200 Corporate Blvd.,
Rockville, MD 20850.

Sec. 814.**106** HDE amendments and resubmitted HDE\'s.

An HDE or HDE supplement may be amended or resubmitted upon an
applicant\'s own initiative, or at the request of FDA, for the same
reasons and in the same manner as prescribed for PMA\'s in Sec. 814.37,
except that the timeframes set forth in Sec. 814.37(c)(1) and (d) do not

apply. If FDA requests an HDE applicant to submit an HDE amendment, and
a written response to FDA\'s request is not received within 75 days of
the date of the request, FDA will consider the pending HDE or HDE
supplement to be withdrawn voluntarily by the applicant. Furthermore, if

the HDE applicant, on its own initiative or at FDA\'s request, submits a
major amendment as described in Sec. 814.37(c)(1), the review period may
be extended up to 75 days.

Sec. 814.**108** Supplemental applications.

After FDA approval of an original HDE, an applicant shall submit
supplements in accordance with the requirements for PMA\'s under Sec.
814.39, except that a request for a new indication for use of a HUD
shall comply with requirements set forth in Sec. 814.110. The timeframes
for review of, and FDA action on, an HDE supplement are the same as
those provided in Sec. 814.114 for an HDE.

Sec. 814.**110** New indications for use.

\(a\) An applicant seeking a new indication for use of a HUD approved
under this subpart H shall obtain a new designation of HUD status in
accordance with Sec. 814.102 and shall submit an original HDE in
accordance with Sec. 814.104.

\(b\) An application for a new indication for use made under Sec.
814.104 may incorporate by reference any information or data previously
submitted to the agency under an HDE.

Sec. 814.**112** Filing an HDE.

\(a\) The filing of an HDE means that FDA has made a threshold
determination that the application is sufficiently complete to permit
substantive review. Within 30 days from the date an HDE is received by
FDA, the agency will notify the applicant whether the application has

been filed. FDA may refuse to file an HDE if any of the following
applies:

\(1\) The application is incomplete because it does not on its face
contain all the information required under Sec. 814.104(b);

\(2\) FDA determines that there is a comparable device available (other
than another HUD approved under this subpart or a device under an
approved IDE) to treat or diagnose the disease or condition for which
approval of the HUD is being sought; or

\(3\) The application contains an untrue statement of material fact or
omits material information.

\(4\) The HDE is not accompanied by a statement of either certification
or disclosure, or both, as required by part 54 of this chapter.

\(b\) The provisions contained in Sec. 814.42(b), (c), and (d) regarding
notification of filing decisions, filing dates, the start of the 75-day
review period, and applicant\'s options in response to FDA refuse to
file decisions shall apply to HDE\'s.

Sec. 814.**114** Timeframes for reviewing an HDE.

Within 75 days after receipt of an HDE that is accepted for filing and
to which the applicant does not submit a major amendment, FDA shall send
the applicant an approval order, an approvable letter, a not approvable
letter (under Sec. 814.116), or an order denying approval

(under Sec. 814.118).

Sec. 814.**116** Procedures for review of an HDE.

\(a\) Substantive review. FDA will begin substantive review of an HDE
after the HDE is accepted for filing under Sec. 814.112. FDA may refer
an original HDE application to a panel on its own initiative, and shall
do so upon the request of an applicant, unless FDA determines that the
application substantially duplicates information previously reviewed by
a panel. If the HDE is referred to a panel, the agency shall follow the
procedures set forth under Sec. 814.44, with the exception that FDA will
complete its review of the HDE and the advisory committee report and

recommendations within 75 days from receipt of an HDE that is accepted
for filing under Sec. 814.112 or the date of filing as determined under
Sec. 814.106, whichever is later. Within the later of these two
timeframes, FDA will issue an approval order under paragraph (b) of this

section, an approvable letter under paragraph (c) of this section, a not
approvable letter under paragraph (d) of this section, or an order
denying approval of the application under Sec. 814.118(a).

\(b\) Approval order. FDA will issue to the applicant an order approving
an HDE if none of the reasons in Sec. 814.118 for denying approval of
the application applies. FDA will approve an application on the basis of
draft final labeling if the only deficiencies in the application concern
editorial or similar minor deficiencies in the draft final labeling.
Such approval will be conditioned upon the applicant incorporating the
specified labeling changes exactly as directed and upon the applicant
submitting to FDA a copy of the final printed labeling before marketing.
The notice of approval of an HDE will be published in the Federal
Register in accordance with the rules and policies applicable to PMA\'s
submitted under Sec. 814.20. Following the issuance of an approval
order, data and information in the HDE file will be available for public
disclosure in accordance with Sec. 814.9(b) through (h), as applicable.

\(c\) Approvable letter. FDA will send the applicant an approvable
letter if the application substantially meets the requirements of this
subpart and the agency believes it can approve the application if
specific additional information is submitted or specific conditions are
agreed to by the applicant. The approvable letter will describe the
information FDA requires to be provided by the applicant or the
conditions the applicant is required to meet to obtain approval. For

example, FDA may require as a condition to approval:

\(1\) The submission of certain information identified in the approvable
letter, e.g., final labeling;

\(2\) Restrictions imposed on the device under section 520(e) of the
act;

\(3\) Postapproval requirements as described in subpart E of this part;
and

\(4\) An FDA inspection that finds the manufacturing facilities,
methods, and controls in compliance with part 820 of this chapter and,
if applicable, that verifies records pertinent to the HDE.

\(d\) Not approvable letter. FDA will send the applicant a not
approvable letter if the agency believes that the application may not be
approved for one or more of the reasons given in Sec. 814.118. The not
approvable letter will describe the deficiencies in the application and,
where practical, will identify measures required to place the HDE in
approvable form. The applicant may respond to the not approvable letter
in the same manner as permitted for not approvable letters for PMA\'s
under Sec. 814.44(f), with the exception that if a major HDE amendment

is submitted, the review period may be extended up to 75 days.

\(e\) FDA will consider an HDE to have been withdrawn voluntarily if:

\(1\) The applicant fails to respond in writing to a written request for
an amendment within 75 days after the date FDA issues such request;

\(2\) The applicant fails to respond in writing to an approvable or not
approvable letter within 75 days after the date FDA issues such letter;
or

\(3\) The applicant submits a written notice to FDA that the HDE has
been withdrawn.

Sec. 814.**118** Denial of approval or withdrawal of approval of an HDE.

\(a\) FDA may deny approval or withdraw approval of an application if
the applicant fails to meet the requirements of section 520(m) of the
act or of this part, or of any condition of approval imposed by an IRB
or by FDA, or any postapproval requirements imposed under Sec. 814.126.

In addition, FDA may deny approval or withdraw approval of an
application if, upon the basis of the information submitted in the HDE
or any other information before the agency, FDA determines that:

\(1\) There is a lack of a showing of reasonable assurance that the
device is safe under the conditions of use prescribed, recommended, or
suggested in the labeling thereof;

\(2\) The device is ineffective under the conditions of use prescribed,
recommended, or suggested in the labeling thereof;

\(3\) The applicant has not demonstrated that there is a reasonable
basis from which to conclude that the probable benefit to health from
the use of the device outweighs the risk of injury or illness, taking
into account the probable risks and benefits of currently available
devices or alternative forms of treatment;

\(4\) The application or a report submitted by or on behalf of the
applicant contains an untrue statement of material fact, or omits
material information;

\(5\) The device\'s labeling does not comply with the requirements in
part 801 or part 809 of this chapter;

\(6\) A nonclinical laboratory study that is described in the HDE and
that is essential to show that the device is safe for use under the
conditions prescribed, recommended, or suggested in its proposed
labeling, was not conducted in compliance with the good laboratory
practice regulations in part 58 of this chapter and no reason for the
noncompliance is provided or, if it is, the differences between the
practices used in conducting the study and the good laboratory practice
regulations do not support the validity of the study;

\(7\) Any clinical investigation involving human subjects described in
the HDE, subject to the institutional review board regulations in part
56 of this chapter or the informed consent regulations in part 50 of
this chapter, was not conducted in compliance with those regulations

such that the rights or safety of human subjects were not adequately
protected;

\(8\) The applicant does not permit an authorized FDA employee an
opportunity to inspect at a reasonable time and in a reasonable manner
the facilities and controls, and to have access to and to copy and
verify all records pertinent to the application; or

\(9\) The device\'s HUD designation should be revoked in accordance with
Sec. 814.102(c).

\(b\) If FDA issues an order denying approval of an application, the
agency will comply with the same notice and disclosure provisions
required for PMA\'s under Sec. 814.45(b) and (d), as applicable.

\(c\) FDA will issue an order denying approval of an HDE after an
approvable or not approvable letter has been sent and the applicant:

\(1\) Submits a requested amendment but any ground for denying approval
of the application under Sec. 814.**118**(a) still applies;

\(2\) Notifies FDA in writing that the requested amendment will not be
submitted; or

\(3\) Petitions for review under section 515(d)(3) of the act by filing
a petition in the form of a petition for reconsideration under Sec.
10.33 of this chapter.

\(d\) Before issuing an order withdrawing approval of an HDE, FDA will
provide the applicant with notice and an opportunity for a hearing as
required for PMA\'s under Sec. 814.46(c) and (d), and will provide the
public with notice in accordance with Sec. 814.46(e), as applicable.

Sec. 814.**120** Temporary suspension of approval of an HDE.

An HDE or HDE supplement may be temporarily suspended for the same
reasons and in the same manner as prescribed for PMA\'s in Sec. 814.47.

Sec. 814.**122** Confidentiality of data and information.

\(a\) Requirement for disclosure. The \`\`HDE file\'\' includes all data
and information submitted with or referenced in the HDE, any IDE
incorporated into the HDE, any HDE amendment or supplement, any report
submitted under Sec. 814.126, any master file, or any other related

submission. Any record in the HDE file will be available for public
disclosure in accordance with the provisions of this section and part 20
of this chapter.

\(b\) Extent of disclosure. Disclosure by FDA of the existence and
contents of an HDE file shall be subject to the same rules that pertain
to PMA\'s under Sec. 814.9(b) through (h), as applicable.

Sec. 814.**124** Institutional Review Board requirements.

\(a\) IRB approval. The HDE holder is responsible for ensuring that a
HUD approved under this subpart is administered only in facilities
having an Institutional Review Board (IRB) constituted and acting
pursuant to part 56 of this chapter, including continuing review of use
of the device. In addition, a HUD may be administered only if such use
has been approved by the IRB located at the facility or by a similarly
constituted IRB that has agreed to oversee such use and to which the
local IRB has deferred in a letter to the HDE holder, signed by the IRB
chair or an authorized designee. If, however, a physician in an
emergency situation determines that approval from an IRB cannot be
obtained in time to prevent serious harm or death to a patient, a HUD
may be administered without prior approval by the IRB located at the
facility or by a similarly constituted IRB that has agreed to oversee
such use. In such an emergency situation, the physician shall, within 5
days after the use of the device, provide written notification to the

chairman of the IRB of such use. Such written notification shall include
the identification of the patient involved, the date on which the device
was used, and the reason for the use.

\(b\) Withdrawal of IRB approval. A holder of an approved HDE shall
notify FDA of any withdrawal of approval for the use of a HUD by a
reviewing IRB within 5 working days after being notified of the
withdrawal of approval.

Sec. 814.**126** Postapproval requirements and reports.

\(a\) An HDE approved under this subpart H shall be subject to the
postapproval requirements and reports set forth under subpart E of this
part, as applicable, with the exception of Sec. 814.82(a)(7). In
addition, medical device reports submitted to FDA in compliance with the

requirements of part 803 of this chapter shall also be submitted to the
IRB of record.

\(b\) In addition to the reports identified in paragraph (a) of this
section, the holder of an approved HDE shall prepare and submit the
following complete, accurate, and timely reports:

\(1\) Periodic reports. An HDE applicant is required to submit reports
in accordance with the approval order. Unless FDA specifies otherwise,
any periodic report shall include:

\(i\) An update of the information required under Sec. 814.102(a) in a
separately bound volume;

\(ii\) An update of the information required under Sec. 814.104(b)(2),
(b)(3), and (b)(5);

\(iii\) The number of devices that have been shipped or sold since
initial marketing approval under this subpart H and, if the number
shipped or sold exceeds 4,000, an explanation and estimate of the number
of devices used per patient. If a single device is used on multiple

patients, the applicant shall submit an estimate of the number of
patients treated or diagnosed using the device together with an
explanation of the basis for the estimate;

\(iv\) Information describing the applicant\'s clinical experience with
the device since the HDE was initially approved. This information shall
include safety information that is known or reasonably should be known
to the applicant, medical device reports made under part 8dd of this

chapter, any data generated from the postmarketing studies, and
information (whether published or unpublished) that is known or
reasonably expected to be known by the applicant that may affect an
evaluation of the safety of the device or that may affect the statement
of contraindications, warnings, precautions, and adverse reactions in
the device\'s labeling; and

\(v\) A summary of any changes made to the device in accordance with
supplements submitted under Sec. 814.108. If information provided in the
periodic reports, or any other information in the possession of FDA,
gives the agency reason to believe that a device raises public health

concerns or that the criteria for exemption are no longer met, the
agency may require the HDE holder to submit additional information to
demonstrate continued compliance with the HDE requirements.

\(2\) Other. An HDE holder shall maintain records of the names and
addresses of the facilities to which the HUD has been shipped,
correspondence with reviewing IRB\'s, as well as any other information
requested by a reviewing IRB or FDA. Such records shall be maintained in

accordance with the HDE approval order.