
[Federal Register Volume 78, Number 37 (Monday, February 25, 2013)]
[Proposed Rules]
[Pages 12664-12675]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-04201]


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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.

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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

[[Page 12665]]

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, 301-796-6563; and
Stephen Ripley, Center for Biologics Evaluation and Research (HFM-17), 
Food and Drug Administration, 1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852-1448, 301-827-6210.

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.

[[Page 12666]]

     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.
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    \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).
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    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.

[[Page 12667]]

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.
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    \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).
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    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

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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

[[Page 12669]]

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

[[Page 12670]]

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

[[Page 12671]]

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).

[[Page 12672]]

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

[[Page 12673]]

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: 202-395-6974, or emailed to oira_submission@omb.eop.gov. 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

[[Page 12674]]

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

[[Page 12675]]

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


