[Federal Register Volume 78, Number 37 (Monday, February 25, 2013)]
[Proposed Rules]
[Pages 12664-12675]
[FR Doc No: 2013-04201]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 807, 812, and 814

[Docket No. FDA-2013-N-0080]
RIN 0910-AG48

Human Subject Protection; Acceptance of Data From Clinical
Studies for Medical Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations on acceptance of data from clinical studies for medical
devices. We are proposing to require that clinical studies conducted
outside the United States as support for an investigational device
exemption (IDE) application, a premarket notification (510(k))
submission, a premarket approval (PMA) application, a product
development protocol (PDP) application, or a humanitarian device
exemption (HDE) application be conducted in accordance with good
clinical practice (GCP), which includes obtaining and documenting the
review and approval of the study by an independent ethics committee
(IEC) and obtaining and documenting freely given informed consent of
study subjects. The proposed rule is intended to update the standards
for FDA acceptance of data from clinical studies conducted outside the
United States and to help ensure the protection of human subjects and
the quality and integrity of data obtained from these studies. As part
of this proposed rule, we are also proposing to amend the IDE and
510(k) regulations to address the requirements for FDA acceptance of
data from clinical studies conducted inside the United States. The
proposed amendments are intended to provide consistency in FDA
requirements for acceptance of clinical data, whatever the application
or submission type.

DATES: Submit either electronic or written comments on the proposed
rule by May 28, 2013. See section VIII of this document for the
proposed effective date of a final rule based on this proposed rule.
Submit comments on information collection issues under the Paperwork
Reduction Act of 1995 by March 27, 2013, (see the ``Paperwork Reduction
Act of 1995'' section of this document).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2013-
N-0080 and/or Regulatory Information Number (RIN) number 0910-AG48, by
any of the following methods, except that comments on information
collection issues under the Paperwork Reduction Act of 1995 (the PRA)
must be submitted to the Office of Information and Regulatory Affairs,
Office of Management and Budget (OMB) (see the ``Paperwork Reduction
Act of 1995'' section of this document):

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following way:
     Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name
and

Docket No. FDA-2013-N-0080 and RIN 0910-AG48 for this rulemaking. All
comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For
additional information on submitting comments, see the ``Request for
Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number(s), found in brackets in the heading of this document,
into the ``Search'' box and follow the prompts and/or go to the
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852.

FOR FURTHER INFORMATION CONTACT:
Sheila Brown, Center for Devices and Radiological Health, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 1651, Silver
Spring, MD 20993,<PHONE_NUMBER>; and
Stephen Ripley, Center for Biologics Evaluation and Research (HFM-17),
Food and Drug Administration, 1401 Rockville Pike, Suite 200N,
Rockville, MD 20852-1448,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. Current Regulations on Clinical Studies for Medical Devices
    B. Reasons for Proposing To Revise the Regulations
II. Description of the Proposed Rule
    A. Definitions
    B. Clinical Studies Conducted Outside the United States
    C. Revisions to Sec.  812.2--Applicability
    D. Requirements for Report of Prior Investigations in IDE
Applications
    E. Requirements for 510(k) Submissions
    F. Requirements for PMA Applications
    G. Correction to the Regulations Regarding Record Retention for
Clinical Studies Conducted Under IDE
III. Legal Authority
IV. Analysis of Economic Impacts
    A. Introduction
    B. Summary
V. Environmental Impact
VI. Paperwork Reduction Act of 1995
VII. Federalism
VIII. Proposed Effective Date
IX. Request for Comments
X. References

I. Background

A. Current Regulations on Clinical Studies for Medical Devices
1. Clinical Studies Conducted Outside the United States
    FDA regulations for PMA of medical devices in part 814 (21 CFR part
814) permit the acceptance of data from clinical studies conducted
outside the United States and submitted in support of a PMA application
if certain conditions are met. Current Sec.  814.15(a) states that a
study conducted outside the United States submitted in support of a PMA
and conducted under an IDE shall comply with part 812 (21 CFR part
812). The provision in Sec.  814.15(a) further states that 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 Sec.  814.15, as applicable.
    Under Sec.  814.15(b), 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 must state in detail any differences between those standards
and the Declaration of Helsinki and explain why they offer greater
protection to the human subjects.
    Under Sec.  814.15(c), FDA will accept studies submitted in support
of a PMA that 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.
    Additionally, Sec.  814.15(d) specifies criteria for acceptance of
a PMA application for marketing approval based solely on foreign
clinical data, and Sec.  814.15(e) encourages applicants to meet with
FDA officials prior to submission of a PMA application that will be
based solely on foreign clinical data.
    Currently, FDA regulations for premarket notification in part 807,
subpart E (21 CFR 807, subpart E), commonly referred to as a ``510(k)
submission,'' and investigational device exemptions in part 812 do not
address the requirements for FDA acceptance of data from clinical
studies conducted outside the United States.
2. Clinical Studies Conducted Inside the United States
    FDA's PMA regulations require applications that include the results
of clinical investigations involving human subjects to include a
statement with respect to each study that: (1) It was conducted in
compliance with the institutional review board regulations in part 56
(21 CFR part 56), or was not subject to those regulations under
Sec. Sec.  56.104 or 56.105, and it was conducted in compliance with
the informed consent regulations in part 50 (21 CFR part 50); or (2) if
the study was not conducted in compliance with those regulations, a
brief statement of the reason for the noncompliance (see Sec.
814.20(b)(6)(ii)(A)). The regulations also require a statement that
each study was conducted in compliance with part 812 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 (Sec.
814.20(b)(6)(ii)(B)).
    Currently, FDA's 510(k) and IDE regulations do not address the
requirements for FDA acceptance of data from clinical studies conducted
inside the United States to support a 510(k) submission or IDE
application.

B. Reasons for Proposing To Revise the Regulations

    FDA believes that the requirements for FDA's acceptance of data
from clinical studies should be consistent regardless of the type of
submission or application in which the data are submitted to FDA. For
data from clinical studies conducted inside the United States, we
propose to require statements in 510(k) submissions and IDE
applications that are similar to those currently required for PMA
applications, to help ensure the protection of human subjects and the
quality and integrity of data obtained from these studies. For data
from clinical studies conducted outside the United States, FDA believes
that revision of the requirements for FDA acceptance of data from these
clinical studies is needed for several reasons, described in this
document.
1. Updating Standards for FDA Acceptance of Data From Clinical Studies
Conducted Outside the United States
    The standards for protecting human subjects have evolved
considerably since the issuance of the PMA regulations in 1986. Several
notable documents have been published (examples listed in this
document) identifying ethical and other principles that provide
assurance of the quality and integrity of clinical data and adequate
protection of human subjects. As a whole, these documents include
principles important to the conduct of clinical trials such as adverse
event reporting, sponsor monitoring, and training of study personnel.

     Several documents issued by the International Conference
on Harmonisation (ICH) of Technical Requirements for Registration of
Pharmaceuticals for Human Use, including the document entitled ``Good
Clinical Practice: Consolidated Guideline'' (ICH E6);
     ``Clinical Investigation of Medical Devices for Human
Subjects--Good Clinical Practice,'' issued by the International
Organization for Standardization, ISO 14155:2011;
     ``Guidelines for Good Clinical Practice (GCP) for Trials
on Pharmaceutical Products,'' issued by the World Health Organization,
1995;
     ``Ethical and Policy Issues in International Research:
Clinical Trials in Developing Countries,'' published by the National
Bioethics Advisory Commission, 2001;
     ``International Ethical Guidelines for Biomedical Research
Involving Human Subjects,'' prepared by the Council for International
Organizations of Medical Sciences in collaboration with the World
Health Organization, 2002;
     ``Good Clinical Practices: Document of the Americas,''
issued by the Pan American Health Organization, 2004; and
     The 1989, 1996, 2000, 2002, 2004, and 2008 amendments to
the ``Declaration of Helsinki on Ethical Principles for Medical
Research Involving Human Subjects,'' adopted by the World Medical
Association.
    Many of these documents articulate ethical and policy standards for
clinical trials, often referred to as GCP. Generally speaking, GCP is
defined by research and regulatory communities as ``a standard for the
design, conduct, performance, monitoring, auditing, recording,
analyses, and reporting of clinical trials that provides assurance that
the data and reported results are credible and accurate, and that the
rights, integrity, and confidentiality of trial subjects are
protected.'' \1\ GCP incorporates important ethical principles, such as
review by an IEC; the need for freely given informed consent; conduct
of clinical trials only by qualified individuals; and recognition that
the rights, safety, and well-being of trial subjects take precedence
over the interests of science and society. GCP enumerates specific
roles and responsibilities of various parties, including monitoring of
the trial and reporting adverse events.
---------------------------------------------------------------------------

    \1\ Definition from the ICH document entitled ``Good Clinical
Practice: Consolidated Guideline'' (ICH E6), which FDA adopted for
use as guidance for industry in 1997 (62 FR 25692, May 9, 1997).
---------------------------------------------------------------------------

    Many of the principles underlying GCP have already been
incorporated in FDA's regulations, including parts 50, 56, 812, and
814. For example, the regulations in subpart B of part 50 contain the
requirements for obtaining the informed consent of human subjects in
clinical investigations. Subparts C and E of part 812 describe the
responsibilities of sponsors and investigators, respectively, regarding
IDE studies, including conformance to parts 50 and 56 on the use of
informed consent and institutional review boards (IRBs), respectively.
FDA considers an IRB, as defined in Sec.  56.102(g) and subject to the
requirements of part 56, to be one type of IEC (see Sec.  312.3 (21 CFR
312.3)).
    We are proposing to revise Sec.  814.15 and to amend parts 807 and
812 to incorporate GCP into the requirements for FDA acceptance of data
from clinical studies conducted outside the United States to support an
IDE or a device marketing application or submission (an application
under sections 515 or 520(m) of the Federal Food, Drug, and Cosmetic
Act (the FD&C Act) (21 U.S.C. 360e and 360j, respectively) or a
premarket notification submission under section 510(k) of the FD&C Act
(21 U.S.C. 360(k)). We believe that the proposed standard helps to
ensure adequate human subject protection and the quality and integrity
of data obtained from such studies, while also being sufficiently
flexible to accommodate differences in how countries regulate the
conduct of clinical research and obtain informed consent.
2. Ensuring Quality and Integrity of Data
    FDA believes that revising parts 807, 812, and 814 to expressly
incorporate GCP will help provide greater assurance of the quality and
integrity of the data obtained from clinical studies conducted outside
the United States and submitted in support of an application or
submission to FDA. It has become increasingly recognized that the
development, recording, and reporting of data that are scientifically
valid are critical responsibilities of investigators and sponsors and
are part of a responsible relationship between these entities and study
subjects. The proposed revisions to parts 807, 812, and 814 should help
ensure data quality and integrity in several ways. These include: (1)
Specifying that GCP includes providing assurance that study data and
reported results are credible and accurate and (2) requiring that
supporting information on a clinical study conducted outside the United
States includes, as appropriate, a description of how the sponsor
monitored the trial and ensured that the study was carried out
consistent with the study protocol.
    The informed consent provisions embodied in GCP also contribute to
the integrity of data obtained in clinical studies. The informed
consent process enables each subject to receive high-quality
information about the implications of participation in the clinical
trial. The process also provides an opportunity for the subject and
investigator to discuss important information about the subject's
condition, potential adverse events, and other factors (such as use of
concurrent therapy, illegal drug use, or alcohol abuse) that could
confound the study results if they remained undisclosed.
3. Standardizing Human Subject Protections
    The current regulations under part 814 require that clinical
studies outside the United States submitted in support of a PMA be
conducted in conformance with the 1983 version of 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
is required to state in detail any differences between those standards
and the 1983 version of the Declaration of Helsinki and explain why
they offer greater protection to the human subjects.
    Under the current regulations, in a study involving multinational
investigational sites, several different standards may be followed
leading to increased complexity in the conduct of the study. The
proposal to require that clinical studies conducted outside the United
States comply with GCP provides a unifying approach, which may simplify
such trials and decrease the regulatory burden on sponsors.
    The investigational new drug regulations in part 312 address FDA
acceptance of foreign clinical studies not conducted under an
investigational new drug application (IND) as support for an IND or
marketing application for a drug or biological product. Effective
October 27, 2008, foreign clinical studies not conducted under an IND
are required to be conducted in accordance with GCP as defined in Sec.
312.120. The proposed revisions to parts 807, 812, and 814 will provide
greater consistency with the regulations for drugs and biological
products regarding FDA acceptance of foreign clinical studies.

4. Clarifying Requirements for FDA Acceptance of Data From Clinical
Studies Submitted in Support of Premarket Notifications and
Investigational Device Exemptions
    Clinical studies may be used to support a 510(k) submission or an
IDE application; however, parts 807 and 812 currently do not address
the requirements for FDA acceptance of data from such studies. The
proposed revisions will identify the requirements for FDA acceptance of
data from clinical studies under these regulations, whether the studies
were conducted inside or outside the United States. This proposal is
intended to ensure the quality and integrity of clinical data submitted
to FDA in 510(k) submissions and IDE applications and to bring
consistency in FDA requirements for acceptance of clinical data,
whatever the application or submission type.

II. Description of the Proposed Rule

A. Definitions

    We propose to add a definition for an IEC to the IDE regulation
under Sec.  812.3. We propose to define an IEC as a ``review panel that
is responsible for ensuring the protection of the rights, safety, and
well-being of human subjects involved in a clinical investigation and
is adequately constituted to provide assurance of that protection.''
Under the proposal, an adequately constituted IEC includes a reasonable
number of members with the qualifications and experience to perform the
IEC's functions. The proposed definition of an IEC also specifies that
an IRB, as defined in Sec.  56.102(g) and subject to the requirements
of part 56, is one type of IEC.

B. Clinical Studies Conducted Outside the United States

    We propose to amend the IDE regulations by adding a new section,
proposed Sec.  812.28, to address the requirements for FDA acceptance
of data from clinical studies conducted outside the United States. An
IDE is typically not issued for a clinical study conducted outside the
United States; however, there is a small subset of trials conducted
outside the United States where IDEs have been issued, for example,
certain studies conducted by the Department of Defense. The use of the
term ``clinical studies conducted outside the United States'' is
intended to address studies not conducted under an IDE and does not
indicate a change in overall policy for device studies conducted
outside the United States.
    The current requirements for FDA acceptance of data from clinical
studies conducted outside the United States in support of a PMA
application are located at Sec.  814.15, in the PMA regulations. We are
proposing to place the revised requirements primarily in the IDE
regulations, in part because the requirements for device clinical
studies are primarily located in these regulations and in part to
create consistency with the drug regulations, which address
requirements for FDA acceptance of foreign clinical data in the
investigational new drug regulations in part 312. Additionally, similar
to these drug regulations, which address requirements for FDA
acceptance of foreign clinical data as support for an IND or marketing
application for a drug or biological product, the proposed revised
device regulations address requirements for FDA acceptance of foreign
clinical data as support for not only a PMA but also an IDE or other
device marketing application or submission, including a 510(k) or an
HDE application.
1. Requirements for FDA Acceptance of Data From Clinical Studies
Conducted Outside the United States
    Proposed Sec.  812.28(a) would identify requirements for FDA
acceptance of data from clinical studies conducted outside the United
States to support an IDE or device marketing application or submission.
It would rely upon conformance with GCP, including review and approval
by an IEC and obtaining and documenting the freely given informed
consent of study subjects. Under proposed Sec.  812.28(a)(1), we would
require a statement that the study was conducted in accordance with
GCP. For purposes of this section, GCP would be defined as a standard
for the design, conduct, performance, monitoring, auditing, recording,
analysis, and reporting of clinical trials in a way that provides
assurance that the data and reported results are credible and accurate
and that the rights, safety, and well-being of trial subjects are
protected. Proposed Sec.  812.28(a)(1) states that GCP includes review
and approval (or provision of a favorable opinion) by an IEC before
initiating a study, continuing review of an ongoing study by an IEC,
and obtaining and documenting the freely given informed consent of a
subject (or the subject's legally authorized representative if the
subject is unable to provide informed consent) before initiating a
study. Proposed Sec.  812.28(a)(1) further states that GCP does not
require informed consent in life-threatening situations when the IEC
reviewing the study finds, before initiation of the study, that
informed consent is not feasible and that either the conditions present
are consistent with those described in Sec. Sec.  50.23 or 50.24(a) of
this chapter (concerning exemptions from informed consent requirements
in life-threatening situations), or the measures described in the study
protocol or elsewhere will protect the rights, safety, and well-being
of subjects. This provision would be consistent with the Good Clinical
Practice guidance,\2\ which recommends that a legally authorized
representative provide informed consent or that the requirement of
informed consent be waived under such circumstances.
---------------------------------------------------------------------------

    \2\ ``Good Clinical Practice: Consolidated Guideline'' (ICH E6),
which FDA adopted for use as guidance for industry in 1997 (62 FR
25692, May 9, 1997).
---------------------------------------------------------------------------

    Proposed Sec.  812.28(a)(2) states the second condition for FDA's
acceptance of data from a clinical study conducted outside the United
States as support for an IDE or a device marketing application or
submission to FDA. A statement would be required assuring the
availability of the data from the study to FDA for validation through
an onsite inspection if the Agency deems it necessary (and an
inspection is otherwise authorized by law) or through other appropriate
means. FDA may need to inspect records relating to data from a foreign
study submitted in support of a PMA, for example, to resolve any
uncertainties about whether the study was conducted in accordance with
GCP.
2. Requirements for Supporting Information
    Proposed Sec.  812.28(b) describes the supporting information to be
submitted, in addition to information required elsewhere in parts 807,
812, and 814, when data from clinical studies conducted outside the
United States are submitted as support for an IDE or device marketing
application or submission. Under proposed Sec.  812.28(b)(1) through
(b)(12), the description of the actions the sponsor or applicant took
to ensure that the research conformed to GCP as described in Sec.
812.28(a)(1) would include the following information:
     Names and addresses of investigators and research
facilities (if an address has changed since the research was conducted,
the address where records are maintained should be provided);
     The investigator's qualifications;
     A description of the research facility(ies);
     A detailed summary of the protocol and results of the
study, and, should FDA request, certified copies of case

records maintained by the investigator or additional background data
such as hospital or other institutional records;
     Either a statement that the device used in the clinical
study conducted outside the United States is identical to the device
that is the subject of the submission or application, or a detailed
description of the device and each important component (including
materials and specifications), ingredient, property, and principle of
operation of the device used in the clinical study conducted outside
the United States and a comparison to the device that is the subject of
the submission or application that indicates how the studied device is
similar to and/or different from the device that is the subject of the
submission or application;
     If the study is intended to support the safety and
effectiveness of a device, a discussion demonstrating that the data and
information constitute valid scientific evidence within the meaning of
Sec.  860.7 (21 CFR 860.7);
     The name and address of the IEC that reviewed the study
and a statement that the IEC meets the definition in Sec.  812.3(t).
The sponsor or applicant must maintain records supporting such a
statement, including records describing the qualifications of IEC
members, and make these records available for Agency review upon
request. Although the names of IEC members are required under Sec.
312.120(b)(6) for foreign clinical studies used to support drug and
biological product applications, we are proposing to require only the
qualifications of the IEC members for device studies due to the
reported difficulties of obtaining the names of IEC members in some
countries;
     A summary of the IEC's decision to approve or modify and
approve the study, or to provide a favorable opinion;
     A description of how informed consent was obtained;
     A description of what incentives, if any, were provided to
subjects to participate in the study;
     A description of how the sponsor(s) monitored the study
and ensured that the study was carried out consistent with the study
protocol; and
     A description of how investigators were trained to comply
with GCP (as described in Sec.  812.28(a)(1)) and to conduct the study
in accordance with the study protocol, and a statement on whether
written commitments by investigators to comply with GCP and the
protocol were obtained. Any written commitments by investigators to
comply with GCP and the study protocol must be maintained by the
sponsor or applicant and made available for Agency review upon request.
    We believe that the proposed supporting information, combined with
an onsite inspection, if necessary, would provide us with the ability
to determine whether a particular clinical study conducted outside the
United States had been conducted in accordance with GCP.
3. Requirements for Records
    Proposed Sec.  812.28(c) describes the retention requirements for
records required by this section with regard to a clinical study
conducted outside the United States. If the study is submitted in
support of an IDE, the records must be retained for 2 years after the
termination or completion of the IDE, as described in proposed Sec.
812.28(c)(1). If the study is submitted in support of a premarket
notification, premarket approval application, a notice of completion of
a product development protocol, or a humanitarian device exemption
application, the records must be retained for 2 years after an Agency
decision on that submission or application, as described in proposed
Sec.  812.28(c)(2).

C. Revisions to Sec.  812.2--Applicability

    We propose to amend Sec.  812.2 by removing current paragraphs
(b)(2) and (e), which refer to requirements that are no longer
necessary because the dates involved have passed. Specifically,
paragraph (b)(2) indicated that investigations of a device, except as
described in paragraph (e), that were begun on or before July 16, 1980,
and were completed on or before January 19, 1981, would be considered
to have approved applications for IDEs, unless FDA notified a sponsor
under Sec.  812.20(a) that approval of an application was required.
    Paragraph (e) required a sponsor who had an IND application for a
device in effect on July 16, 1980, and who wished to continue the
investigation after 90 days after that date, to comply with paragraph
(b)(1) if not a significant risk device or obtain FDA approval under
Sec.  812.30 of an IDE application.
    To accommodate the proposed removal of paragraph (b)(2), paragraphs
(b) and (b)(1) would be combined and proposed paragraph (b) states that
unless FDA has notified a sponsor under Sec.  812.20(a) that approval
of an application is required, an investigation of a device other than
a significant risk device is considered to have an approved application
for IDE, if the device is not a banned device and the sponsor complies
with paragraphs (b)(1) through (b)(7). Note that paragraphs (b)(1)
through (b)(7) are the proposed redesignated paragraphs (b)(1)(i)
through (b)(1)(vii).
    The current IDE regulations identify varying requirements for
clinical investigations of devices based on whether the study is of a
significant risk or nonsignificant risk device or would meet the
exemption requirements in Sec.  812.2(c). We propose that requirements
for clinical studies conducted outside the United States, which are to
be submitted to FDA in support of an IDE or a device marketing
application or submission, also be subject to varying requirements,
depending on whether the study is of a significant risk device or
nonsignificant risk device or would meet the exemption requirements in
Sec.  812.2(c).
    Proposed paragraph (e) identifies these varying requirements.
Proposed Sec.  812.2(e)(1) requires studies of a significant risk
device, as defined in Sec.  812.3(m), to comply with the requirements
of the principles of good clinical practice, as defined in Sec.
812.28(a), maintenance of supporting information as described in Sec.
812.28(b), and records retention as described in Sec.  812.28(c).
Proposed Sec.  812.2(e)(2) requires studies of a device, other than a
significant risk device, or clinical device investigations that would
otherwise meet the exemption requirements in Sec.  812.2(c), to comply
with these same requirements concerning good clinical practice and
records retention, but with lesser requirements concerning maintenance
of the supporting information (i.e., only those requirements at Sec.
812.28(b)(1), (4), (5), (7), (8), (9), and (11)), in recognition of
their differing regulatory status compared to significant risk device
investigations.

D. Requirements for Report of Prior Investigations in IDE Applications

    Current Sec.  812.27(a) requires the report of prior investigations
to include reports of all prior clinical, animal, and laboratory
testing of the device but does not include specific requirements for
reports of clinical testing. Proposed Sec.  812.27(b)(4) would describe
the specific requirements for reports of clinical testing conducted
both inside and outside the United States.
    Proposed (b)(4)(i) requires that, if information on clinical
studies conducted in the United States is provided, the report of prior
investigations shall include a statement that all such studies have
been conducted in compliance with applicable requirements in the
protection of human subjects regulations in part 50, the institutional

review boards regulations in part 56, and the investigational device
exemptions regulations in part 812, or if any such study was not
conducted in compliance with such regulations, a brief statement of the
reason for the noncompliance. It also provides that failure or
inability to comply with these requirements does not justify failure to
provide information on a relevant clinical study.
    Proposed Sec.  812.27(b)(4)(ii) states, if information on clinical
studies conducted outside the United States is provided to support an
IDE, the requirements under Sec.  812.2(e) and Sec.  812.28 of this
chapter apply, where the requirements for such studies are detailed. If
any such study was not conducted in accordance with GCP as described in
Sec.  812.28(a), the report of prior investigations shall include a
brief statement of the reason for not conducting the study in
accordance with GCP and a description of steps taken to assure that the
data and reported results are credible and accurate and that the
rights, safety, and well-being of trial subjects were protected. This
description is necessary for studies conducted outside the United
States because of the greater difficulty in conducting bioresearch
monitoring inspections of foreign sites. It further states that failure
or inability to comply with these requirements does not justify failure
to provide information on a relevant clinical study.
    We remind sponsors and applicants that they must submit all studies
and other information required under applicable FDA regulations for
medical devices. For example, as part of our review of an IDE, we
consider all relevant data bearing on the safe use of the proposed
medical device, including data obtained in any clinical studies
conducted outside the United States--even data from studies that are
not carried out in accordance with GCP.

E. Requirements for 510(k) Submissions

    The requirements for premarket notifications are described in part
807, subpart E. The information required in a premarket notification
submission is detailed at Sec.  807.87, but this section does not
discuss the requirements relating to clinical data submitted, where
applicable, to support a premarket notification submission. Most
premarket notifications do not include clinical data and would not be
affected by this proposed rule; however, we believe the requirements
for FDA acceptance of clinical data should be the same for premarket
notifications that do contain clinical data as for other device
applications in order to achieve consistency in FDA's clinical data
requirements. For 510(k) submissions relying upon literature only, the
proposed requirements at new Sec.  807.87(j) would not generally apply.
    For the subset of premarket notifications that do contain clinical
data, we propose to add a new paragraph (j) to describe requirements
relating to clinical data submitted to support a premarket notification
and to redesignate existing paragraph (j) as paragraph (k), existing
paragraph (k) as paragraph (l), and existing paragraph (l) as paragraph
(m).
    For a premarket notification submission containing clinical data,
proposed paragraph (j)(1) requires, if the data are from clinical
studies conducted in the United States, a statement that each study was
conducted in compliance with applicable requirements in parts 50, 56,
and 812 of this chapter, or if the study was not conducted in
compliance with those regulations, a brief statement of the reason for
the noncompliance.
    Proposed paragraph (j)(2) states that, if the data are from
clinical studies conducted outside the United States, the requirements
under Sec.  812.2(e) and Sec.  812.28 of this chapter apply. If any
such study was not conducted in accordance with GCP as described in
Sec.  812.28(a), the submission must include a brief statement of the
reason for not conducting the study in accordance with GCP and a
description of steps taken to assure that the data and reported results
are credible and accurate and that the rights, safety, and well-being
of trial subjects were protected. This description is necessary for
studies conducted outside the United States because of the greater
difficulty in conducting bioresearch monitoring inspections of foreign
sites. This proposal will help ensure consistency in FDA clinical data
requirements, whatever the type of product application or submission at
issue.

F. Requirements for PMA Applications

    The requirements for premarket approval are described in part 814.
The requirements for FDA acceptance of clinical data submitted in
support of a PMA from studies conducted outside the United States are
currently addressed in Sec.  814.15. As previously indicated, we
propose to address these requirements primarily in the IDE regulations.
Therefore, removal of current paragraphs (a), (b), and (c) in Sec.
814.15 is proposed. Proposed paragraph (a) will identify the general
requirement that a study conducted outside the United States and
submitted in support of a PMA shall comply with the relevant provisions
of part 812 as set forth in Sec.  812.2(e) and Sec.  812.28. To
accommodate this change, current paragraphs (d) and (e) will be
redesignated as paragraphs (b) and (c) respectively.
    To address the requirements for PMA applications that include data
from clinical studies conducted outside the United States, we propose
to amend Sec.  814.20(b), the content requirements for a PMA
application, specifically the requirements for technical sections
containing results of clinical investigations in paragraph (6)(ii). We
propose to add a new subparagraph (C) stating that, for clinical
studies conducted outside the United States intended to support the
PMA, the requirements under Sec.  812.2(e) and Sec.  812.28 of this
chapter apply. Required information may be incorporated by cross-
reference to another section of the application that contains such
information. If any such study was not conducted in accordance with GCP
as described in Sec.  812.28(a), the application must include a brief
statement of the reason for not conducting the study in accordance with
GCP and a description of steps taken to assure that the data and
reported results are credible and accurate and that the rights, safety,
and well-being of trial subjects were protected. This description is
necessary for studies conducted outside the United States because of
the greater difficulty in conducting bioresearch monitoring inspections
of foreign sites. We remind sponsors and applicants that failure or
inability to comply with these requirements does not justify failure to
provide information concerning investigations bearing on the safety or
effectiveness of a device undergoing PMA review (see Sec.
814.20(b)(8)(ii) and sections 515(c)(1)(A) and 515(c)(2)(A)(v) of the
FD&C Act).
    We also propose to amend the provisions in Sec.  814.45 concerning
denial of approval of a PMA application. We propose to revise paragraph
(a)(5) to include as a reason for denial that any clinical
investigation involving human subjects described in the PMA
application, which was subject to GCP referenced in Sec.  814.15(a) and
described in Sec.  812.28(a), was not conducted in compliance with
those regulations such that the rights or safety of human subjects were
not adequately protected or the supporting data were determined to be
otherwise unreliable.
    Further, we propose to amend Sec.  814.46 regarding withdrawal of
approval of a PMA application, specifically to revise paragraph (a)(4)
to allow FDA to withdraw approval if FDA

determines that any clinical investigation involving human subjects
described in the PMA application, subject to GCP referenced in Sec.
814.15(a) and described in Sec.  812.28(a), was not conducted in
compliance with those regulations such that the rights or safety of
human subjects were not adequately protected or the supporting data
were determined to be otherwise unreliable.
    Finally, we propose to amend Sec.  814.104 regarding the required
contents of HDE applications. Although these applications remain
subject to modified requirements for application contents compared to
premarket approval applications, we propose that they would not be
exempt from the new proposed requirement in Sec.  814.20(b)(6)(ii)(C)
regarding submission of data from clinical studies conducted outside
the United States. The proposed language also clarifies that, in those
situations where data from clinical studies conducted inside the United
States are submitted in support of a HDE application, the requirements
in Sec.  814.20(b)(6)(ii)(A)-(B) apply.
    Premarket approval is considered to include a PDP declared to be
completed by FDA (see Sec.  814.19 and section 515(f) of the FD&C Act).
Although PDPs are rarely submitted, if a PDP is supported by data from
clinical studies conducted outside the United States, the requirements
in Sec.  814.15 would apply.

G. Correction to the Regulations Regarding Record Retention for
Clinical Studies Conducted Under IDE

    When the regulations for premarket approval were amended to address
HDE applications, the IDE regulations were not amended because at the
time clinical studies supporting an HDE application were not
anticipated (largely because of the small numbers of patients affected
and the infeasibility of conducting large, randomized clinical trials).
Experience has demonstrated that many HDE applications do include data
from clinical studies (usually from small, non-randomized studies) in
order to meet the required standard for approval. Therefore, we are
proposing to revise Sec.  812.140(d) regarding retention of records for
clinical research conducted under an IDE to include records supporting
an HDE application.
    We are similarly proposing to revise Sec.  812.140(d) regarding
retention of records for clinical research conducted under an IDE to
include records supporting a premarket notification submission, where
applicable. Most premarket notification submissions do not include
clinical data. For the subset that do contain clinical data, we are
proposing that record retention requirements be the same as for other
product applications and submissions that contain clinical data, to
ensure consistency in FDA clinical data requirements and the integrity
and reliability of clinical data submitted. This proposed revision to
Sec.  812.140(d) is also consistent with proposed Sec.  812.28(c),
described in this document, regarding retention of records for clinical
research conducted outside the United States. Each of these proposed
revisions would achieve consistency in FDA requirements for clinical
data record retention regardless of the application or submission type.

III. Legal Authority

    We are proposing to issue this rule under the authority of the
provisions of the FD&C Act that apply to medical devices (21 U.S.C. 301
et seq.).
    To permit devices to be shipped for investigational use, section
520(g) of the FD&C Act authorizes the exemption of investigational
devices from otherwise applicable provisions of the FD&C Act relating
to misbranding, registration, premarket notification, performance
standards, premarket approval, banned devices, records and reporting
requirements, good manufacturing practice requirements, and
requirements relating to the use of color additives in devices. Under
section 520(g) of the FD&C Act, the procedures and conditions that FDA
\3\ is authorized to prescribe for granting an IDE include the
requirement that an application be submitted to FDA, in such form and
manner as the Agency shall specify, and other requirements necessary
for the protection of the public health and safety. Section 520(g) also
requires that the information submitted in support of an IDE
application be ``adequate to justify the proposed clinical testing.''
In investigations involving human subjects, the person applying for the
exemption (the sponsor) must comply with a number of requirements to
assure that the rights and safety of subjects are adequately protected.
To provide for flexibility in regulatory requirements, section 520(g)
of the FD&C Act permits variations in the procedures and conditions
governing IDEs, depending on the nature, scope, duration, and purpose
of the study.
---------------------------------------------------------------------------

    \3\ In light of section 1003(d) of the FD&C Act (21 U.S.C.
393(d)) and the Secretary of Health and Human Services' (the
Secretary's) delegation to the Commissioner of Food and Drugs,
statutory references to ``the Secretary'' in the discussion of legal
authority have been changed to ``FDA'' or the ``Agency.''
---------------------------------------------------------------------------

    Section 515(c)(1)(A) of the FD&C Act requires that PMA applications
contain, among other information, full reports of all information,
published or known to or which should reasonably be known to the PMA
applicant, concerning investigations bearing on the safety or
effectiveness of the device for which premarket approval is sought.
Section 515(d)(2) of the FD&C Act states that FDA shall deny approval
of a PMA application if the Agency finds that ``there is a lack of a
showing of reasonable assurance that such device is safe under the
conditions of use prescribed, recommended, or suggested in the proposed
labeling thereof'' or ``there is a lack of a showing of reasonable
assurance that the device is effective under the conditions of use
prescribed, recommended, or suggested in the proposed labeling
thereof,'' among other reasons. Whether data from an investigation
involving human subjects support the safety or effectiveness of a
device depends, in part, on whether the study was conducted in
accordance with ethical and other principles that provide assurance of
the quality and integrity of clinical data and adequate protection of
human subjects. Even if the data derive from improperly conducted
clinical studies, the data must be submitted in a PMA application under
section 515(c)(1)(A) of the FD&C Act.
    Under section 513(i) of the FD&C Act (21 U.S.C. 360c(i)),
determinations of substantial equivalence include some inquiry into the
comparable safety and effectiveness of the device, where appropriate.
For devices that have the same intended use as the predicate device but
different technological characteristics, information submitted to
demonstrate substantial equivalence must include ``appropriate clinical
or scientific data[,] if deemed necessary'' by FDA, showing that ``the
device is as safe and effective as a legally marketed device'' and
``does not raise different questions of safety and effectiveness than
the predicate device.'' As described in this document, whether data
from a clinical study support the safety or effectiveness of a device--
or, in the context of some premarket notifications, the comparable
safety and effectiveness of a device as part of a substantial
equivalence demonstration--depends in part on whether the study was
conducted in accordance with ethical and other principles that provide
assurance of the quality and integrity of clinical data and adequate
protection of human subjects.
    Under section 520(m) of the FD&C Act, FDA may grant an HDE if FDA
finds that: The device is designed to treat or diagnose a disease or
condition that affects fewer than 4,000 individuals in the United
States; the device would

not be available to a person with such disease or condition unless FDA
grants the exemption and there is no comparable device, other than
under this exemption, available to treat or diagnose such disease or
condition; and the device will not expose patients to an unreasonable
or significant risk of illness or injury and 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. Again, whether data from clinical studies submitted in an
HDE application support that the probable benefits of the device
outweigh its risks depends, in part, on whether the study was conducted
in accordance with ethical and other principles that provide assurance
of the quality and integrity of clinical data and adequate protection
of human subjects.
    Section 701(a) of the FD&C Act (21 U.S.C. 371(a)) authorizes the
Agency to issue regulations for the efficient enforcement of the FD&C
Act.
    These statutory provisions authorize us to issue regulations
describing when we may consider data from clinical trials, whether
conducted inside or outside the United States, as reliable evidence
supporting an IDE, PMA, 510(k), PDP, or HDE application or submission.

IV. Analysis of Economic Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The Agency believes that this proposed rule is not a
significant regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the requirements are likely to impose a
burden on a substantial number of affected small entities, the Agency
projects that the proposed rule, if finalized, will have a significant
economic impact on a substantial number of small entities, and has
conducted an Initial Regulatory Flexibility Analysis as required under
the Regulatory Flexibility Act.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $139 million, using the most current (2011) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.

B. Summary

    The proposed rule will require that clinical studies conducted
outside the United States and used to support IDE applications, 510(k)
submissions, PMA applications, HDE applications, or PDP applications
comply with GCP. GCP standards include review and approval by an
independent ethics committee and obtaining and documenting human
subjects' informed consent. In addition, the proposed rule seeks to
amend the 510(k), HDE, and IDE requirements for FDA acceptance of data
from clinical studies conducted inside the United States to parallel
existing FDA requirements for PMA applications. FDA has not quantified
the benefits of the proposed rule that would come from increased
collection of information that would provide FDA with greater assurance
of clinical data quality and human subject protection, particularly as
it pertains to clinical studies conducted outside the United States.
Costs would arise from increased labor costs associated with obtaining,
documenting, and maintaining records to meet the proposed requirements.
The estimated costs of complying with these requirements range from
$0.30 million to $24.03 million.
    The full analysis of economic impacts is available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (See also Ref. 1).

V. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by the OMB under the PRA (44 U.S.C. 3501-3520). A
description of these provisions is given in the Description section of
this document with an estimate of the annual reporting and
recordkeeping burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
    FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Human Subject Protection; Data Requirements for Medical
Device Related Clinical Studies
    Description: In this document is a discussion of the regulatory
provisions we believe are subject to the PRA and the probable
information collection burden associated with these provisions.
    Description of Respondents: The reporting and recordkeeping
requirements referenced in this document are imposed on a device
sponsor or applicant.
Section 807.87 Information Required in a Premarket Notification
Submission (OMB Control No. 0910-0120)
    Section 807.87 is being amended to address requirements for 510(k)
submissions supported by clinical data. For clinical studies conducted
in the United States, submitters will be required to submit a statement
as described in Sec.  807.87(j)(1). For clinical studies conducted
outside the United States, submitters will be required to submit a
statement as described in Sec.  807.87(j)(2).

Section 812.2 Clinical Studies Conducted Outside the United States (OMB
Control No. 0910-0078)
    For any clinical studies conducted outside the United States to be
submitted in support of: (1) An IDE, (2) a PMA, (3) a PDP, (4) an HDE
or (5) a 510(k), the sponsor or applicant will be required to maintain
supporting information and retain records as described in Sec.
812.2(e).
Section 812.27 Report of Prior Investigations (OMB Control No. 0910-
0078)
    Section 812.27 is being amended to address requirements for IDE
applications supported by clinical data. For clinical studies conducted
in the United States, sponsors will be required to submit a statement
as described in Sec.  812.27(b)(4)(i). For clinical studies conducted
outside the United States, sponsors will be required to submit a
statement as described in Sec.  812.27(b)(4)(ii).
Section 812.28 Clinical Studies Conducted Outside the United States
(OMB Control No. 0910-NEW)
    Section 812.28 is being proposed to address the requirements for
acceptance of foreign clinical data to support an IDE or a device
marketing application or submission. The sponsor or applicant will be
required to submit statements as described in Sec.  812.28(a)(1) and
(a)(2); provide a description of the actions the sponsor or applicant
took to ensure that the research conformed to GCP that includes the
information in Sec.  812.28(b)(1) through (b)(12) or a cross-reference
to another section of the submission where the information is located;
and retain the records as described in Sec.  812.28(c).
Section 812.140 Records Retention (OMB Control No. 0910-0078)
    Section 812.140 is being amended to address record retention
requirements for investigators and sponsors. An investigator or sponsor
will be required to maintain records as described in Sec.  812.140(d).
Section 814.20 Application (OMB Control No. 0910-0231)
    Section 814.20 is being amended to address requirements for a PMA
supported by data from clinical studies conducted outside the United
States. The applicant will be required to submit a statement and
information as required by Sec.  814.20(b)(6)(ii)(C).
Section 814.104 Original Applications (OMB Control No. 0910-0332)
    Section 814.104 is being amended to address submission of data from
clinical studies in an HDE. To the extent the applicant includes
clinical information, the applicant will be required to include the
information and statements described in Sec.  814.104(b)(4)(i).

                                 Table 1--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                   Number of
        21 CFR Section             Number of     responses per   Total annual    Average burden     Total hours
                                  respondents     respondent       responses      per response
----------------------------------------------------------------------------------------------------------------
807.87........................           1,500               1           1,500  0.25 (15                     375
                                                                                minutes).
812.27(b)(4)(i)...............             400               1             400  1...............             400
812.27(b)(4)(ii)..............             100               1             100  0.25 (15                      25
                                                                                minutes).
812.28(a)(1)..................           1,500               1           1,500  0.25 (15                     375
                                                                                minutes).
812.28(a)(2)..................           1,500               1           1,500  0.25 (15                     375
                                                                                minutes).
812.28(b).....................           1,500               1           1,500  10..............          15,000
814.20........................              10               1              10  0.50 (30                       5
                                                                                minutes).
814.104.......................              10               1              10  8...............              80
                               ---------------------------------------------------------------------------------
    Total.....................  ..............  ..............  ..............  ................          16,635
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

                          Table 2--(Ongoing) Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
         21 CFR Section              Number of      records per    Total annual         per         Total hours
                                   recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
812.2(e)........................             500               1             500               1             500
812.28(c).......................           1,500               1           1,500               1           1,500
812.140.........................              10               1              10               1              10
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............           2,010
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

The total estimated burden imposed by these information collection
requirements is 18,645 annual hours. The estimated burden is based on
the most recent empirical data in the relevant collections with the
numbers updated to reflect the current burden of these requirements.

    It should be noted that while the information collection
requirements referenced in this document are revisions to current
approved information collections, these collection requirements are
being submitted to OMB as a new information collection, with the
expectation the currently approved requirements will be amended. As
such the following collections of information will be amended and
submitted to OMB for approval as revisions to currently approved
information collections once the rule is finalized and the collections
are due for renewal. The collections to be amended include:
Investigational Device Exemptions Reports and Records--21 CFR part 812,
OMB control number 0910-0078; Premarket Notification--21 CFR part 807,
subpart E, OMB control number 0910-0120; Premarket Approval of Medical
Devices--21 CFR part 814, OMB control number 0910-0231; and Medical

Devices: Humanitarian Use Device--21 CFR part 814, subpart H, OMB
control number 0910-0332.
    To ensure that comments on these new information collection
requirements are received, OMB recommends that written comments be
faxed to the Office of Information and Regulatory Affairs, OMB, Attn:
FDA Desk Officer, FAX:<PHONE_NUMBER>, or emailed to<EMAIL_ADDRESS>All comments should be identified with the
title ``Human Subject Protection; Data Requirements for Medical Device
Related Clinical Studies.''
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), the Agency has submitted the information collection
provisions of this proposed rule to OMB for review. These requirements
will not be effective until FDA obtains OMB approval. FDA will publish
a notice concerning OMB approval of these requirements in the Federal
Register.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.

VIII. Proposed Effective Date

    We propose that any final rule based on this proposal become
effective 180 days after the final rule is published in the Federal
Register.

IX. Request for Comments

    Interested persons may submit either electronic comments regarding
this document to http://www.regulations.gov or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

X. Reference

    The following reference has been placed on display in the Division
of Dockets Management (see ADDRESSES) and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday, and are
available electronically at http://www.regulations.gov.
    1. Preliminary Regulatory Impact Analysis of the Proposed Rule to
Human Subject Protection; Acceptance of Data From Clinical Studies for
Medical Devices, Docket No. FDA-2013-N-0080.

List of Subjects

21 CFR Part 807

    Confidential business information, Imports, Medical devices,
Reporting and recordkeeping requirements.

21 CFR Part 812

    Health records, Medical devices, Medical research, Reporting and
recordkeeping requirements.

21 CFR Part 814

    Administrative practice and procedure, Confidential business
information, Medical devices, Medical research, Reporting and
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, FDA proposes
that 21 CFR parts 807, 812, and 814 be amended as follows:

PART 807--ESTABLISHMENT REGISTRATION AND DEVICE LISTING FOR
MANUFACTURERS AND INITIAL IMPORTERS OF DEVICES

0
1. The authority citation for 21 CFR part 807 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 360, 360c, 360e, 360i,
360j, 371, 374, 381, 393; 42 U.S.C. 264, 271.

0
2. Section 807.87 is amended by redesignating paragraphs (j), (k), and
(l) as paragraphs (k), (l), and (m), respectively, and by adding new
paragraph (j) to read as follows:

Sec.  807.87  Information required in a premarket notification
submission.

* * * * *
    (j) For a submission containing clinical data:
    (1) If the data are from clinical studies conducted in the United
States, a statement that each study was conducted in compliance with
applicable requirements in the protection of human subjects regulations
in part 50 of this chapter, the institutional review boards regulations
in part 56 of this chapter, and the investigational device exemptions
regulations in part 812 of this chapter, or if the study was not
conducted in compliance with those regulations, a brief statement of
the reason for the noncompliance.
    (2) If the data are from clinical studies conducted outside the
United States, the requirements under Sec. Sec.  812.2(e) and 812.28 of
this chapter apply. If any such study was not conducted in accordance
with good clinical practice (GCP) as described in Sec.  812.28(a),
include a brief statement of the reason for not conducting the study in
accordance with GCP and a description of steps taken to assure that the
data and reported results are credible and accurate and that the
rights, safety, and well-being of trial subjects were protected.
* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

0
3. The authority citation for 21 CFR part 812 continues to read as
follows:

    Authority: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c-360f,
360h-360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C. 216, 241,
262, 263b-263n.

0
4. Section 812.2 is amended by removing paragraphs (b) introductory
text, (b)(1) introductory text, (b)(2), and (e); redesignating
paragraphs (b)(1)(i) through (b)(1)(vii) as paragraphs (b)(1) through
(b)(7), respectively; and adding new paragraphs (b) introductory text
and (e) to read as follows:

Sec.  812.2  Applicability.

* * * * *
    (b) Abbreviated requirements. Unless FDA has notified a sponsor
under Sec.  812.20(a) that approval of an application is required, an
investigation of a device other than a significant risk device is
considered to have an approved application for IDE if the device is not
a banned device and the sponsor:
* * * * *
    (e) Clinical studies conducted outside the United States. Clinical
studies conducted outside the United States to be submitted in support
of an IDE or a device marketing application or submission (an
application under section 515 or 520(m) of the Federal Food, Drug, and
Cosmetic Act or a premarket notification submission under section
510(k) of the Federal Food, Drug, and Cosmetic Act), are subject to the
following requirements:
    (1) For a significant risk device, as defined in Sec.  812.3(m),
the principles of

good clinical practice, as defined in Sec.  812.28(a), maintenance of
supporting information as described in Sec.  812.28(b), and records
retention as described in Sec.  812.28(c).
    (2) For a device, other than a significant risk device, or a device
investigation that would otherwise meet the exemption requirements in
Sec.  812.2(c), the principles of good clinical practice, as defined in
Sec.  812.28(a), maintenance of the supporting information as described
in Sec.  812.28(b)(1), (b)(4), (b)(5), (b)(7), (b)(8), (b)(9), and
(b)(11), and records retention as described in Sec.  812.28(c).

0
5. Section 812.3 is amended by adding paragraph (t) to read as follows:

Sec.  812.3  Definitions.

* * * * *
    (t) Independent ethics committee (IEC) means a review panel that is
responsible for ensuring the protection of the rights, safety, and
well-being of human subjects involved in a clinical investigation and
is adequately constituted to provide assurance of that protection. An
institutional review board (IRB), as defined in Sec.  56.102(g) of this
chapter and subject to the requirements of part 56 of this chapter, is
one type of IEC.

0
6. Section 812.27 is amended by adding paragraph (b)(4) to read as
follows:

Sec.  812.27  Report of prior investigations.

* * * * *
    (b) * * *
    (4)(i) If information on clinical studies conducted in the United
States is provided, a statement that all such studies have been
conducted in compliance with applicable requirements in the protection
of human subjects regulations in part 50 of this chapter, the
institutional review boards regulations in part 56 of this chapter, and
the investigational device exemptions regulations in part 812, or if
any such study was not conducted in compliance with such regulations, a
brief statement of the reason for the noncompliance. Failure or
inability to comply with these requirements does not justify failure to
provide information on a relevant clinical study.
    (ii) If information on clinical studies conducted outside the
United States is provided to support the IDE, the requirements under
Sec. Sec.  812.2(e) and 812.28 apply. If any such study was not
conducted in accordance with good clinical practice (GCP) as described
in Sec.  812.28(a), the report of prior investigations shall include a
brief statement of the reason for not conducting the study in
accordance with GCP and a description of steps taken to assure that the
data and reported results are credible and accurate and that the
rights, safety, and well-being of trial subjects were protected.
Failure or inability to comply with these requirements does not justify
failure to provide information on a relevant clinical study.
0
7. Section 812.28 is added to subpart B to read as follows:

Sec.  812.28  Clinical studies conducted outside the United States.

    (a) Acceptance of data from clinical studies conducted outside the
United States to support an IDE or a device marketing application or
submission (an application under section 515 or 520(m) of the Federal
Food, Drug, and Cosmetic Act or a premarket notification submission
under section 510(k) of the Federal Food, Drug, and Cosmetic Act). FDA
will accept information on clinical studies conducted outside the
United States to support an IDE or a device marketing application or
submission if the data are valid, the information specified in
paragraph (b) of this section and required elsewhere in parts 807, 812,
and 814 of this chapter, as applicable, is submitted, and the following
conditions are met:
    (1) A statement is provided that all such studies have been
conducted in accordance with good clinical practice (GCP). For the
purposes of this section, GCP is defined as a standard for the design,
conduct, performance, monitoring, auditing, recording, analysis, and
reporting of clinical trials in a way that provides assurance that the
data and reported results are credible and accurate and that the
rights, safety, and well-being of trial subjects are protected. GCP
includes review and approval (or provision of a favorable opinion) by
an independent ethics committee (IEC) before initiating a study,
continuing review of an ongoing study by an IEC, and obtaining and
documenting the freely given informed consent of the subject (or a
subject's legally authorized representative, if the subject is unable
to provide informed consent) before initiating a study. GCP does not
require informed consent in life-threatening situations when the IEC
reviewing the study finds, before initiation of the study, that
informed consent is not feasible and either that the conditions present
are consistent with those described in Sec. Sec.  50.23 or 50.24(a) of
this chapter, or that the measures described in the study protocol or
elsewhere will protect the rights, safety, and well-being of subjects.
    (2) A statement is provided assuring the availability of the data
from the study to FDA for validation through an onsite inspection if
the Agency deems it necessary, and if otherwise authorized by law, or
through other appropriate means.
    (b) Supporting information. A sponsor or applicant who submits data
from a clinical study conducted outside the United States in support of
an IDE or a device marketing application or submission, in addition to
information required elsewhere in parts 807, 812, and 814 of this
chapter, as applicable, shall provide a description of the actions the
sponsor or applicant took to ensure that the research conformed to GCP
as described in paragraph (a)(1) of this section. The description is
not required to duplicate information already submitted in the
application or submission. Instead, the description must provide either
the following information or a cross-reference to another section of
the application or submission where the information is located:
    (1) Names and addresses of investigators and research facilities;
    (2) The investigator's qualifications;
    (3) A description of the research facility(ies);
    (4) A detailed summary of the protocol and results of the study
and, should FDA request, certified copies of case records maintained by
the investigator or additional background data such as hospital or
other institutional records;
    (5) Either a statement that the device used in the study conducted
outside the United States is identical to the device that is the
subject of the submission or application, or a detailed description of
the device and each important component (including all materials and
specifications), ingredient, property, and principle of operation of
the device used in the study conducted outside the United States and a
comparison to the device that is the subject of the submission or
application that indicates how the studied device is similar to and/or
different from the device that is the subject of the submission or
application;
    (6) If the study is intended to support the safety and
effectiveness of a device, a discussion demonstrating that the data and
information constitute valid scientific evidence within the meaning of
Sec.  860.7 of this chapter;
    (7) The name and address of the IEC that reviewed the study and a
statement that the IEC meets the definition in Sec.  812.3(t). The
sponsor or applicant must maintain records supporting such statement,
including records describing

the qualifications of IEC members, and make these records available for
Agency review upon request;
    (8) A summary of the IEC's decision to approve or modify and
approve the study, or to provide a favorable opinion;
    (9) A description of how informed consent was obtained;
    (10) A description of what incentives, if any, were provided to
subjects to participate in the study;
    (11) A description of how the sponsor(s) monitored the study and
ensured that the study was carried out consistently with the study
protocol; and
    (12) A description of how investigators were trained to comply with
GCP (as described in paragraph (a)(1) of this section) and to conduct
the study in accordance with the study protocol, and a statement on
whether written commitments by investigators to comply with GCP and the
protocol were obtained. Any signed written commitments by investigators
must be maintained by the sponsor or applicant and made available for
Agency review upon request.
    (c) Records. A sponsor or applicant must retain the records
required by this section for a clinical study conducted outside the
United States as follows:
    (1) If the study is submitted in support of an IDE, for 2 years
after the termination or completion of the IDE;
    (2) If the study is submitted in support of a premarket
notification submission, premarket approval application, a notice of
completion of a product development protocol, or a humanitarian device
exemption application, for 2 years after an Agency decision on that
submission or application.
0
8. Section 812.140 is amended by revising paragraph (d) to read as
follows:

Sec.  812.140  Records.

* * * * *
    (d) Retention period. An investigator or sponsor shall maintain the
records required by this subpart during the investigation and for a
period of 2 years after the latter of the following two dates: The date
on which the investigation is terminated or completed, or the date that
the records are no longer required for purposes of supporting a
premarket approval application, a notice of completion of a product
development protocol, a humanitarian device exemption application, or a
premarket notification submission.
* * * * *

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

0
9. The authority citation for 21 CFR part 814 continues to read as
follows:

    Authority: 21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372,
373, 374, 375, 379, 379e, 381.

0
10. Section 814.15 is amended by removing paragraphs (b) and (c); by
redesignating paragraph (d) as paragraph (b) and paragraph (e) as
paragraph (c); and by revising paragraph (a) to read as follows:

Sec.  814.15  Research conducted outside the United States.

    (a) A clinical study conducted outside the United States and
submitted in support of a PMA shall comply with the relevant provisions
of part 812 of this chapter as set forth in Sec. Sec.  812.2(e) and
812.28 of this chapter.
* * * * *
0
11. Section 814.20 is amended by adding paragraph (b)(6)(ii)(C) to read
as follows:

Sec.  814.20  Application.

* * * * *
    (b) * * *
    (6) * * *
    (ii) * * *
    (C) For clinical studies conducted outside the United States that
are intended to support the PMA, the requirements under Sec. Sec.
812.2(e) and 812.28 of this chapter apply. Required information may be
incorporated by cross-reference to another section of the application
that contains such information. If any such study was not conducted in
accordance with good clinical practice (GCP) as described in Sec.
812.28(a) of this chapter, include a brief statement of the reason for
not conducting the study in accordance with GCP and a description of
steps taken to assure that the data and reported results are credible
and accurate and that the rights, safety, and well-being of trial
subjects were protected. Failure or inability to comply with these
requirements does not justify failure to provide information on a
relevant clinical study.
* * * * *
0
12. Section 814.45 is amended by revising paragraph (a)(5) to read as
follows:

Sec.  814.45  Denial of approval of a PMA.

    (a) * * *
    (5) Any clinical investigation involving human subjects described
in the PMA, subject to the institutional review board regulations in
part 56 of this chapter or informed consent regulations in part 50 of
this chapter or GCP referenced in Sec.  814.15(a) and described in
Sec.  812.28(a) of this chapter, was not conducted in compliance with
those regulations such that the rights or safety of human subjects were
not adequately protected or the supporting data were determined to be
otherwise unreliable.
* * * * *
0
13. Section 814.46 is amended by revising paragraph (a)(4) to read as
follows:

Sec.  814.46  Withdrawal of approval of a PMA.

    (a) * * *
    (4) Any clinical investigation involving human subjects described
in the PMA, subject to the institutional review board regulations in
part 56 of this chapter or informed consent regulations in part 50 of
this chapter or GCP referenced in Sec.  814.15(a) and described in
Sec.  812.28(a) of this chapter, was not conducted in compliance with
those regulations such that the rights or safety of human subjects were
not adequately protected or the supporting data were determined to be
otherwise unreliable.
* * * * *
0
14. Section 814.104 is amended by revising paragraph (b)(4)(i) to read
as follows:

Sec.  814.104  Original applications.

* * * * *
    (b) * * *
    (4) * * *
    (i) In lieu of the summaries, conclusions, and results from
clinical investigations required under Sec.  814.20(b)(3)(v)(B),
(b)(3)(vi), and the introductory text of (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 to the extent the
applicant includes such clinical information, the applicant shall
include the statements described in Sec.  814.20(b)(6)(ii)(A) and
(b)(6)(ii)(B) with respect to clinical investigations conducted in the
United States and the information described in Sec.
814.20(b)(6)(ii)(C) with respect to clinical investigations conducted
outside the United States; and
* * * * *

    Dated: February 20, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-04201 Filed 2-22-13; 8:45 am]
BILLING CODE 4160-01-P