[Federal Register Volume 83, Number 35 (Wednesday, February 21, 2018)]
[Rules and Regulations]
[Pages 7366-7388]
[FR Doc No: 2018-03244]

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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
Investigations for Medical Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or we) is amending its
regulations on acceptance of data from clinical investigations for
medical devices. We are requiring that data submitted from clinical
investigations conducted outside the United States intended to support
an investigational device exemption (IDE) application, a premarket
notification (510(k)) submission, a request for De Novo classification,
a premarket approval (PMA) application, a product development protocol
(PDP) application, or a humanitarian device exemption (HDE) application
be from investigations conducted in accordance with good clinical
practice (GCP), which includes obtaining and documenting the review and
approval of the clinical investigation by an independent ethics
committee (IEC) and obtaining and documenting freely given informed
consent of subjects, which includes individuals whose specimens are
used in investigations of medical devices. The final rule updates the
criteria for FDA acceptance of data from clinical investigations
conducted outside the United States to help ensure the quality and
integrity of data obtained from these investigations and the protection
of human subjects. As part of this final rule, we are also amending the
IDE, 510(k), and HDE regulations to address the requirements for FDA
acceptance of data from clinical investigations conducted inside the
United States. The final rule provides consistency in FDA requirements
for acceptance of data from clinical investigations, whatever the
application or submission type.

DATES: This rule is effective February 21, 2019. See section III of
this document for additional explanation of the effective date of this
final rule.

FOR FURTHER INFORMATION CONTACT: Soma Kalb, Director, Investigational
Device Exemptions Staff, Office of Device Evaluation, Center for
Devices and Radiological Health, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 66, Rm. 1534, Silver Spring, MD 20993, 301-
796-6359; and Stephen Ripley, Center for Biologics Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
71, Rm. 7301, Silver Spring, MD 20993,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of the Final Rule

    Through this rule, FDA is updating the standards for FDA acceptance
of data from clinical investigations conducted outside the United
States to help ensure the quality and integrity of data obtained from
these investigations and the protection of human subjects. In this
rule, FDA is amending the regulations for PMA applications, HDE
applications, IDE applications, and premarket notification submissions.
As part of this rule, FDA also is amending the IDE regulations and the
premarket notification regulations to address the requirements for FDA
acceptance of data from clinical investigations conducted inside the
United States. The amendments are intended to provide consistency in
FDA requirements for acceptance of clinical data, whatever the
application or submission type.

Legal Authority

    FDA is issuing this rule under the authority of the provisions of
the Federal Food, Drug, and Cosmetic Act (FD&C Act) that apply to
medical devices (21 U.S.C. 301 et seq.), including section 520(g)
regarding IDEs (21 U.S.C. 306j(g)), section 515(c)(1)(A) and (d)(2)
regarding PMAs (21 U.S.C. 360e(c)(1)(A) and (d)(2)), sections 510(k)
and 513(i) regarding premarket notifications and determinations of
substantial equivalence (21 U.S.C. 360(k) and 360c(i), respectively),
section 520(m) regarding HDEs, section 513(f)(2) regarding De Novo
classifications, section 569B regarding acceptance of data from
clinical investigations conducted outside the United States (21 U.S.C.
360bbb-8b), and section 701(a) regarding regulations for the efficient
enforcement of the FD&C Act (21 U.S.C. 371(a)).

Summary of the Major Provisions of the Final Rule

    This rule requires that sponsors and applicants of submissions and
applications that include clinical investigations conducted outside the
United States and submitted to support an IDE or device marketing
application or submission provide statements and information regarding
how the

investigations conform with GCP. FDA defines GCP as a standard for the
design, conduct, performance, monitoring, auditing, recording,
analysis, and reporting of clinical investigations in a way that
provides assurance that the data and results are credible and accurate
and that the rights, safety, and well-being of subjects are protected.
GCP includes review and approval by an IEC before initiating an
investigation, continuing IEC review of ongoing investigations, and
obtaining and documenting the freely given informed consent of
subjects. FDA also is including requirements for the acceptance of data
from clinical investigations conducted in the United States submitted
to support an IDE application, an HDE application, or a premarket
notification submission. The changes require a statement regarding
compliance with FDA regulations for human subject protection,
institutional review boards, and IDEs when the investigations are
conducted in the United States. With the above described changes, the
rule is intended to update the standards for FDA acceptance of data
from clinical investigations and to help ensure the quality and
integrity of data obtained from these investigations and the protection
of human subjects.

Summary of Costs and Benefits

    The total estimated annualized costs of complying with these
requirements, over 10 years, range from $0.8 million to $22.1 million
with a 7 percent discount rate and range from $0.7 million to $22.0
million with a 3 percent discount rate. We lack data to quantify
benefits, but expect the final rule will provide greater assurance of
clinical data quality and integrity and human subject protection.

Table of Contents

I. Background
II. Overview of the Final Rule
III. Effective Date
IV. Comments on the Proposed Rule
    A. International Harmonization
    B. Application of the Rule
    C. Non-Compliant Studies
    D. In Vitro Diagnostic (IVD) Devices
    E. Independent Ethics Committee
    F. Acceptance of Data From Clinical Investigations Conducted
Outside the United States
    G. Onsite Inspection
    H. Supporting Information
    I. Record Retention
    J. Denial or Withdrawal of PMA
    K. Implementation
    L. Guidance Needed
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. Reference

I. Background

    In the Federal Register of February 25, 2013 (78 FR 12664), FDA
issued a proposed rule to revise the regulations in parts 807, 812, and
814 (21 CFR parts 807, 812, and 814) on the conditions under which FDA
will accept data from clinical studies as support for an IDE
application, a 510(k) submission, a PMA application, a PDP application,
or an HDE application. The proposed rule addressed revisions to update
the criteria for acceptance of data from clinical studies to help
ensure the quality and integrity of data obtained from those studies
and the protection of human subjects. In particular, the proposed rule
addressed revisions to part 814 to update the criteria for acceptance
of data from clinical studies conducted outside the United States. The
proposed rule also addressed revisions to parts 807, 812, and 814,
subpart H, to identify criteria for acceptance of data from clinical
studies conducted both inside and outside the United States. The
proposed rule identified similar criteria for acceptance of clinical
data for all application and submission types for medical devices.
    FDA received comments on the proposed rule from 13 entities: 7
medical device manufacturers, 2 academia, 2 associations, 1 drug
manufacturer, and 1 consumer. The comments were supportive of GCP for
medical devices as a mechanism to help ensure the quality and integrity
of the data obtained from clinical investigations and human subject
protection. Comments generally supported FDA's efforts to clarify the
criteria for acceptance of clinical data submitted to FDA to support an
IDE or a device marketing application or submission. Many comments,
however, raised concerns about the proposed rule and some believed the
rule was premature.

II. Overview of the Final Rule

    FDA considered all comments received on the proposed rule and we
have made several important changes, primarily for clarity and
accuracy, to reduce burden, and to provide flexibility in meeting
regulatory requirements. The main changes from the proposed rule
include:
     Deleting proposed Sec.  812.2(e) because comments received
indicated confusion regarding the scope of the rule. Proposed Sec.
812.2(e) described the principles of good clinical practice applicable
to studies conducted outside the United States that will be submitted
to FDA in support of an IDE or device marketing application or
submission. Including this information within the applicability section
of the IDE regulations led some to believe that FDA intended for part
812 to apply to all clinical investigations conducted outside the
United States. We have deleted proposed Sec.  812.2(e) and included the
supporting information requirements for clinical investigations
conducted outside the United States in new Sec.  812.28(a)(2).
     Clarifying that the rule applies to clinical data from
``investigations'' as defined in Sec.  812.3(h) rather than using other
terms, such as ``clinical study'' and ``clinical trial,'' in an
interchangeable manner.
     Clarifying that the rule applies to the acceptance of data
from clinical investigations conducted outside the United States when
submitted to support an IDE or a device marketing application or
submission rather than to all clinical data contained in such
applications or submissions.
     Adding new Sec.  812.28(a)(2), which identifies different
supporting information requirements based on whether the investigation
is for a significant risk device or a non-significant risk device, or
meets the exemption criteria in Sec.  812.2(c). Also, for
investigations meeting the exemption criteria in Sec.  812.2(c), the
specified supporting information is required to be maintained and be
made available for Agency review upon request by FDA.
     Adding a requirement in new Sec.  812.28(a)(2) that the
sponsor's or applicant's rationale for considering an investigation to
be of a non-significant risk device or to meet the exemption criteria
in Sec.  812.2(c) be made available upon request by FDA. We also
clarify in the preamble that we do not expect foreign IECs to provide
oversight of the significant risk versus non-significant risk device
determination and that sponsors and applicants may proceed based upon
their own determination or based on a determination by FDA.
     Changing the requirements related to supporting
information on incentives provided to subjects to require that the
information be maintained for all clinical investigations but only
require submission for significant risk device investigations. For
investigations of non-significant risk devices and investigations
meeting the exemption criteria in Sec.  812.2(c), the final rule
requires that information on incentives be made available upon FDA's
request. We made this change because of concerns that incentives can
affect data integrity for all investigations. We do not believe this
requirement will be

overly burdensome. Informed consent documents usually describe
incentives and the IEC reviews this information. Therefore, providing
the description of incentives to FDA should not be a burden. FDA will
allow some flexibility in how sponsors or applicants comply with this
provision. If the informed consent form includes an explanation of any
incentives provided to subjects, a sponsor or applicant could submit a
model consent form to meet the requirement. Alternatively, a sponsor or
applicant could also satisfy the requirement by submitting a
description of any incentives provided to subjects to participate in
the investigation.
     Adding a waiver provision in new Sec.  812.28(c) to allow
sponsors and applicants to request a waiver of any applicable
requirements under Sec.  812.28(a)(1) and (b) if adequate justification
can be provided. Although we believe the rule is flexible enough to
address concerns about compliance with the laws and regulations of
other countries and in situations when the sponsor or applicant did not
initiate or conduct the clinical investigations, this revision will
allow sponsors and applicants to request a waiver if they can provide
adequate justification. Although the proposed rule included provisions
that would allow a sponsor or applicant to explain why a clinical
investigation was not conducted in accordance with GCP when submitted
in support of an IDE or a device marketing application or submission,
addition of the waiver provision would allow sponsors and applicants to
request a waiver prior to submitting an application or submission
supported by clinical data from investigations conducted outside the
United States. A waiver may be requested prior to initiation of an
investigation. The waiver provision requires a sponsor or applicant to
justify a waiver request and allows FDA to decide whether to grant or
deny a waiver on a case-by-case basis, taking into account all
appropriate circumstances, based on whether or not the waiver would be
in the interest of public health.
     Adding a provision in new Sec.  812.28(e) to clarify that,
for clinical investigations conducted outside the United States that do
not meet the conditions under Sec.  812.28(a), FDA may accept the
information from such clinical investigations to support an IDE or a
device marketing application or submission if FDA believes that the
data and results from such clinical investigations are credible and
accurate and that the rights, safety, and well-being of subjects have
been adequately protected. Although this was implied in the provisions
of the proposed rule allowing a sponsor or applicant to explain why a
clinical investigation was not conducted in accordance with GCP, new
Sec.  812.28(e) makes this clear.
     Modifying the definition of an IEC in Sec.  812.3(t) by
changing the reference to the definition of an institutional review
board (IRB). In the proposed rule, we referenced Sec.  56.102(g) (21
CFR 56.102(g)). In the final rule, we reference Sec.  812.3(f), which
incorporates Sec.  56.102(g), because Sec.  812.3(f) is specific to
devices. While these definitions vary slightly, we interpret the
definitions as having the same meaning. We have elected to reference
the definition in Sec.  812.3(f) in order to reference definitions in
part 812 whenever possible.
     Changing the requirement in proposed Sec.  812.28(a)(2),
now Sec.  812.28(a)(3), that a statement is provided assuring the
availability of the data from the study to FDA for validation through
an onsite inspection to a requirement that FDA is able to validate the
data from the investigation through an onsite inspection if the Agency
deems it necessary.
     Amending Sec. Sec.  812.28 and 812.140(d) to clarify that
these provisions apply to requests for De Novo classifications, which
are a type of device marketing submission. FDA intended for Sec. Sec.
812.28 and 812.140(d) to encompass all device marketing applications
and submissions. As stated in the proposed rule, ``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'' (78 FR 12664 at
12665). This amendment will provide for consistency by ensuring that
FDA requirements for acceptance of data from clinical investigations
conducted outside the United States are the same for all device
marketing applications and submissions, and will help to provide
greater assurance of the quality and integrity of the data from such
investigations submitted in support of this type of device marketing
submission.

III. Effective Date

    In response to comments, and after consideration of the intent and
purpose of the new requirements, we have determined that the effective
date will be 1 year after the publication of this final rule in the
Federal Register. This final rule will apply to all clinical
investigations that enroll the first subject on or after the effective
date of this rule and that support an IDE or a device marketing
application or submission to FDA. For the purposes of this rule, a
subject is considered enrolled when the subject, or the subject's
legally authorized representative, agrees to participate in a clinical
investigation as indicated by signing of the informed consent
document(s), or participates in an investigation meeting the
requirements of Sec.  50.24 (21 CFR 50.24).
    If an investigation conducted outside the United States enrolled
the first subject prior to the rule's effective date, then the
requirements in Sec.  814.15 (21 CFR 814.15) prior to the rule's
effective date would apply. Specifically, if data from clinical
investigations conducted outside the United States that enrolled the
first subject prior to the effective date of this rule are submitted in
support of a PMA application, FDA will accept the data if the data are
valid and the investigator has conducted the studies in conformance
with the ``Declaration of Helsinki'' or the laws and regulations of the
country in which the research is conducted, whichever accords greater
protection to the human subjects. If the standards of the country are
used, the applicant shall state in detail any differences between those
standards and the ``Declaration of Helsinki'' and explain why they
offer greater protection to the human subjects. (See Sec.  814.15(b).)
    In section IV.K of this document, we discuss the effective date
further in our response to the comments concerning the implementation
of the rule.

IV. Comments on the Proposed Rule

    A summary of the comments submitted to the docket and our responses
follow. To make it easier to identify comments and our responses, the
word ``Comment,'' in parentheses, will appear before each comment; and
the word ``Response,'' in parentheses, will appear before each
response. We have numbered the comments to make it easier to
distinguish between comments. The numbers are for organizational
purposes only and do not reflect the order in which we received the
comments or any value associated with them. We have combined similar
comments under one numbered comment.

A. International Harmonization

    Section 812.28(a) of the proposed rule would identify criteria for
FDA acceptance of data from clinical studies conducted outside the
United States and submitted in support of an IDE or a device marketing
application or submission. Those criteria would require that such
studies be conducted in accordance with GCP. This

requirement would replace the requirement in the PMA regulations that
studies be conducted in conformance with the Declaration of Helsinki or
the laws and regulations of the country in which the research is
conducted, whichever accord greater protection to human subjects. The
requirement would be new for IDE applications and other device
marketing applications and submissions that previously did not address
acceptance of data from clinical studies conducted outside the United
States.
    (Comment 1) Several comments raised concerns that FDA was not
seeking a harmonized global approach to the regulation of medical
devices. Comments raised concerns with various aspects of the proposed
rule, such as a harmonized GCP standard, definitions of various terms,
and expectations for requirements.
    (Response) FDA disagrees. The rule only addresses the criteria for
FDA acceptance of clinical data submitted to FDA that support an IDE or
a device marketing application or submission. The rule does not address
other aspects of medical device regulations, such as when an
application or submission must be supported by clinical data, the type
of clinical data needed, etc.
    FDA has and will continue to promote global harmonization in many
aspects of medical device development and regulation. With respect to
medical device good clinical practice, FDA's international activities
include harmonizing regulatory requirements with our foreign
counterparts, industry, and other international stakeholders. For
example, FDA plays a key role in forums such as the International
Medical Device Regulators Forum (IMDRF) where global medical device
good clinical practice was discussed during the IMDRF meeting in
Florianopolis, Brazil, in September 2016. Additionally, FDA continues
to be directly involved in good clinical practice standard development,
including those of the International Organization for Standardization
(ISO) and the International Conference on Harmonisation (ICH).
    (Comment 2) Several comments raised concerns that an
internationally accepted GCP standard for medical devices does not
exist and the rule should not be finalized until harmonized
international GCP guidelines for medical devices have been established.
They note that the ICH E6 GCP guidelines for pharmaceuticals were
developed through a collaborative approach involving international
regulators and drug and biological product manufacturers with all
stakeholders having an equal voice. They state that such guidelines do
not exist for medical devices and that FDA should first seek a
collaborative global approach and establishment of a harmonized
guidance through the IMDRF organization, or similar group, with
industry participation.
    (Response) FDA disagrees that there has not been global
collaboration in the development of a GCP standard for medical devices.
The ``Clinical Investigation of Medical Devices for Human Subjects-Good
Clinical Practice'' standard, ISO 14155:2011, represents an
international GCP standard for medical devices that FDA has recognized
(March 16, 2012, 77 FR 15765). FDA acknowledges that the standard
development processes are different between ICH and ISO, but notes that
several countries participated in the development of ISO 14155:2011,
including Australia, Belgium, Brazil, Canada, China, France, Ireland,
Italy, Japan, Spain, the United Kingdom, and the United States. Several
medical device companies also participated in the standard development
process. Additionally, ISO 14155:2011 is recognized by most of the
members of the IMDRF (Australia, Brazil, Canada, European Union, Japan,
and the United States) as well as other countries, including Indonesia,
Malaysia, Singapore, Thailand, and Taiwan.
    FDA's rule does not identify a specific GCP standard for sponsors
and applicants to follow. Instead, the rule includes a definition of
GCP in Sec.  812.28(a)(1), which is consistent with the definition in
Sec.  312.120 (21 CFR 312.120), that embodies well recognized GCP
principles and has been generally accepted. This allows sponsors of
clinical investigations conducted outside the United States to
determine an appropriate GCP standard to use for clinical
investigations that will produce data to support an IDE or a device
marketing application or submission to FDA. The rule helps to ensure
that the data and results from such investigations are credible and
accurate and that the rights, safety, and well-being of human subjects
are adequately protected, while also being sufficiently flexible to
accommodate differences in how countries regulate the conduct of
clinical investigations.
    (Comment 3) One comment suggested that once a harmonized GCP
guideline is adopted, many of the requirements should be waived for
countries that adopt the harmonized GCP guideline.
    (Response) FDA disagrees with this suggestion. For FDA acceptance
of data from clinical investigations conducted outside the United
States to support an IDE or a device marketing application or
submission, the rule requires, among other things, that sponsors and
applicants provide a statement that the investigation was conducted in
accordance with GCP and provide supporting information. If these
requirements were waived, a submission or application would not contain
information regarding the sponsor's or applicant's conformity with GCP.
The fact that the country where the investigation is conducted had
adopted a GCP guideline would only identify the GCP guideline that
should be followed but would not provide information regarding
conformity of the clinical investigation with the GCP guideline.
    (Comment 4) Two comments raised a concern that the rule may run
into resistance from foreign regulators and clinical communities who
may interpret the rule as FDA unilaterally imposing FDA GCP standards
on them. Two other comments were concerned that the rule may conflict
with the rules and regulations of other countries. A fifth comment
stated that FDA does not have the authority to regulate the conduct of
studies conducted outside the United States.
    (Response) FDA does not intend to regulate clinical investigations
conducted outside the United States. The rule only identifies the
criteria for FDA acceptance of clinical data submitted to FDA to
support an IDE or a device marketing application or submission. We have
modified the rule by removing proposed Sec.  812.2(e) to clarify that
the rule does not apply part 812 to investigations conducted outside
the United States but rather addresses the conditions for FDA
acceptance of clinical data when submitted to support an IDE or device
marketing application or submission. FDA expects that foreign clinical
investigations will be conducted in accordance with local laws and
regulations. The application of a GCP standard would be in addition to
the local laws and regulations to the extent that the local laws and
regulations do not incorporate such a standard.
    FDA's rule does not identify a specific GCP standard for sponsors
and applicants to follow. Instead, the rule includes a definition of
GCP in Sec.  812.28(a)(1), which is consistent with the definition in
Sec.  312.120, that embodies well recognized GCP principles and has
been generally accepted. Although the rule does not identify a specific
GCP standard, we note that ISO 14155:2011, a GCP standard for medical
devices that FDA has recognized, includes provisions for meeting local
requirements. FDA

believes that sponsors and applicants who follow ISO 14155:2011 in the
conduct of clinical investigations will be able to meet the requirement
in Sec.  812.28(a)(1) of this rule as well as the local laws and
regulations of the countries where the investigations are conducted.
    FDA believes the requirements outlined in the rule allow the
flexibility needed to accommodate the laws and regulations of other
countries. We also believe that conducting a clinical investigation
according to a standard that meets the definition of GCP as provided in
the rule will help to ensure the integrity and quality of the data and
the protection of subjects. If needed, the rule allows sponsors and
applicants to explain why GCP was not followed and to describe the
steps taken to ensure that the data and results are credible and
accurate and that the rights, safety, and well-being of human subjects
have been adequately protected. Additionally, we have added a waiver
provision to allow sponsors and applicants to request a waiver from any
applicable requirement in Sec.  812.28(a)(1) and (b) of the rule (see
new Sec.  812.28(c)). If a country's clinical investigation
requirements are not congruent with the GCP definition in this rule or
with a GCP standard and the sponsor or applicant cannot meet GCP for
the investigation, they may provide an explanation of the departure
from GCP or request a waiver. FDA will take this information into
account when considering the extent to which the Agency can rely on the
data from these clinical investigations on a case-by-case basis.

B. Application of the Rule

    (Comment 5) Several comments raised concerns that the rule may be
interpreted as expanding the types of studies required to be included
in applications and submissions and requiring GCP for all studies. Some
comments requested clarification of the use of the terms ``clinical
investigation,'' ``clinical study,'' and ``clinical trial'' in a
seemingly interchangeable manner. The comments noted that the terms
``clinical study'' and ``clinical trial'' are not defined but the term
``investigation'' is defined in Sec.  812.3(h).
    (Response) While FDA intended that ``clinical study'' and
``clinical trial'' have the same meaning as ``clinical investigation,''
to avoid any confusion, FDA has revised the rule to use the term
``clinical investigation'' with the meaning as defined in Sec.
812.3(h) (``Investigation means a clinical investigation or research
involving one or more subjects to determine the safety or effectiveness
of a device.''). We have also revised the rule to clarify that it
applies when data from clinical investigations are provided to support
an IDE or a device marketing application or submission; for example,
when clinical data are submitted in: (1) A 510(k) submission to
demonstrate substantial equivalence, (2) a PMA application to
demonstrate a reasonable assurance of safety and effectiveness, or (3)
an HDE application to demonstrate reasonable assurance of safety and
probable benefit. When clinical data from investigations are included
in applications and submissions as supplementary information and not as
support, demonstration of conformity with GCP is not required.
    (Comment 6) One comment noted that the proposed rule identified
different requirements for acceptability of results from clinical
investigations depending on the location of the study, that is, inside
or outside the United States. The comment indicated applying this
differential regimen would be difficult when a multicenter clinical
investigation has sites both inside and outside the United States. The
comment recommended that the requirements should not apply to clinical
investigations per se but to clinical data. This would allow data
originating from within the United States to be subject to existing GCP
regulations (for example, parts 50, 56, and 812 (21 CFR parts 50, 56,
and 812)) and data originating from outside the United States to be
subject to the new GCP provisions even if the data were part of the
same clinical investigation.
    (Response) FDA notes that for a multicenter investigation with
sites both inside and outside the United States, each site would need
to comply with the local requirements. Clinical investigations
conducted in the United States to determine the safety or effectiveness
of a device are subject to parts 50, 56, and 812. The rule does not
govern investigational sites located outside the United States, but
rather specifies the criteria for FDA acceptance of data from
investigations conducted outside the United States to support an IDE or
device marketing application or submission. When a multicenter
investigation includes sites both inside and outside the United States,
the sponsor or applicant may provide a statement regarding the
international nature of the investigation, the compliance of sites with
their applicable local requirements, and a statement regarding
conformance with GCP along with the required supporting information.
    (Comment 7) Two comments noted that Sec.  812.2(e) identifies
requirements for non-significant risk device investigations but IECs
from other countries may not be familiar with this terminology and
classification and may be unable to provide oversight of the sponsor's
determination as in the United States. One comment recommended that
sponsors use their own determinations.
    (Response) FDA agrees with these comments and notes that the
significant risk versus non-significant risk determination in the rule
relates only to the supporting information required to be submitted and
maintained by sponsors and applicants while the requirement to follow
GCP applies to all investigations submitted to FDA in support of device
applications and submissions. As discussed previously, we have removed
proposed Sec.  812.2(e) but we have maintained the provisions for
different supporting information requirements in new Sec.
812.28(a)(2).
    FDA does not intend that foreign IECs provide oversight of the
significant risk versus non-significant risk determination. FDA
recognizes that IECs outside the United States may not be familiar with
FDA's terminology related to significant risk and non-significant risk
device investigations. Under the IDE regulations, sponsors may make an
initial determination. Similarly, sponsors and applicants may make an
initial determination for investigations conducted outside the United
States. If the sponsor or applicant proceeds based on their own
determination, they should maintain documentation of the rationale for
their determination because FDA may request it, as stipulated at Sec.
812.28(a)(2).
    For multinational investigations that include sites in the United
States, the determination of the IRBs overseeing the sites in the
United States should be used. In addition, sponsors and applicants may
request a determination from FDA, just as they may for investigations
conducted in the United States.
    Note that any determination made by FDA, whether requested or not,
will supersede any determination made by the sponsor or applicant (or
IRB, if the sponsor or applicant relied on an IRB's determination). If
FDA determines that an investigation is of a significant risk device
that was submitted as an investigation of a non-significant risk device
or exempt investigation, FDA may request the additional supporting
information required for significant risk device investigations.
Likewise, if FDA determines that an investigation is of a non-
significant risk device that was submitted as an exempt investigation,
FDA may request the additional

supporting information required for non-significant risk device
investigations.
    (Comment 8) One comment recommended that the same requirements for
IDE exempt studies apply regardless of where the study sites are
located. The comment stated that studies exempt under Sec.  812.2(c)
are not required to meet any requirements of part 812 except Sec.
812.119 when conducted in the United States, while the proposed rule
levies a long list of requirements for these same studies when
conducted outside the United States.
    (Response) FDA agrees in principle with the comment. We acknowledge
that the supporting information to be submitted in an application or
submission could be viewed as greater when data from clinical
investigations conducted outside the United States are provided to
support an IDE or device marketing application or submission than when
data from clinical investigations conducted inside the United States
that meet the exemption criteria in Sec.  812.2(c) are provided to
support an IDE or device marketing application or submission. While we
have deleted proposed Sec.  812.2(e), new Sec.  812.28(a)(2) includes a
paragraph that addresses the supporting information requirements for
device investigations that would meet the exemption criteria in Sec.
812.2(c), as well as paragraphs addressing the supporting information
to be provided for significant risk and non-significant risk device
investigations. The supporting information requirements for
investigations that meet the exemption criteria now only require that
this information be made available upon request. That is, the
information is not required to be included in an IDE or device
marketing application or submission unless FDA requests the
information.
    In Sec.  812.28(a), we require that clinical investigations
conducted outside the United States and submitted to support an IDE or
device marketing application or submission be conducted in accordance
with GCP as defined in Sec.  812.28(a)(1). GCP includes review and
approval (or provision of a favorable opinion) by an IEC and obtaining
and documenting the freely given informed consent of the subject (or
the subject's legally authorized representative if the subject is
unable to provide informed consent). Similarly, FDA notes that
investigations conducted in the United States that are exempt under
Sec.  812.2(c) are still required to comply with parts 50 and 56,
regarding informed consent and IRB review, when the data support
applications or submissions to FDA.

C. Non-Compliant Studies

    (Comment 9) One comment questioned the need for a statement in IDE
applications and 510(k) submissions regarding compliance of clinical
studies conducted in the United States with parts 50, 56, and 812. The
comment stated that FDA must approve IDE applications, so it is not
clear why data from a study that is run according to an approved IDE
would not be acceptable for clinical studies conducted inside the
United States.
    (Response) FDA disagrees with the comment. Not all clinical
investigations of medical devices in the United States require an IDE
application to be submitted to FDA. Investigations conducted under the
abbreviated IDE requirements in Sec.  812.2(b) or under the exemptions
in Sec.  812.2(c) do not require submission of an IDE application to
FDA. Therefore, a clinical investigation could be conducted in the
United States without FDA's review and approval of an IDE application.
The statement required in Sec. Sec.  807.87(j)(1) and 812.27(b)(4)(i)
mirrors the statement required in Sec.  814.20(b)(6)(ii) for PMA
applications supported by clinical data from investigations conducted
in the United States. Requiring this statement also provides
consistency with the new requirements that apply when data from
clinical investigations conducted outside the United States are
provided to support an IDE or device marketing application or
submission by providing assurance that the investigations conducted
inside the United States were conducted in compliance with FDA's GCP
regulations. These statements will aid FDA in assessing the quality and
integrity of the clinical data and the protection of human subjects.
    (Comment 10) A comment noted that compliance with the IDE, IRB, and
informed consent regulations are not always required for all clinical
studies but if a study should have complied and did not, this is a
compliance matter and FDA's determination on an application or
submission should not be held up.
    (Response) FDA disagrees that a clinical investigation that was not
conducted in compliance with regulatory requirements is solely a
compliance matter. As a result of noncompliance there may be serious
concerns related to data quality or integrity, the safety of subjects,
or with the device itself that would prevent FDA's review of the
application from moving forward. FDA does not intend to withhold a
determination on an application or submission when it is possible to
render a determination irrespective of an outstanding compliance issue.
However, data from a clinical investigation that was not conducted in a
manner that ensures that the data and results are credible and accurate
and that the rights, safety, and well-being of human subjects have been
adequately protected can impact FDA's ability to render a
determination. The information required by the rule will assist FDA in
determining whether the clinical data are unreliable and may not be
used to support an application or submission.
    (Comment 11) Several comments indicated that FDA should not exclude
from consideration data from studies that were not conducted in
accordance with GCP. These comments identified a number of reasons why
a study may not comply with GCP or the sponsor or applicant may not
have information on how the study was conducted. Many comments did not
object to providing information describing the extent to which the
principles of GCP were followed and suggested alternative language for
the rule.
    (Response) FDA agrees, in general, that data from clinical
investigations that were not conducted in conformity with GCP may still
provide useful information and could be relied upon to make regulatory
decisions. The intent of the rule is not to disallow the use of data
from certain investigations but rather to ensure FDA's decisions are
based on scientifically valid and ethically derived data. Conformance
with GCP is one way to help ensure clinical data are credible,
accurate, and ethically procured.
    The rule includes provisions that allow a sponsor or applicant to
provide an explanation if the investigation was not conducted in
accordance with GCP. These provisions are in Sec. Sec.  807.87(j),
812.27(b)(4), and 814.20(b)(6)(ii). If an investigation was not
conducted in accordance with GCP, these provisions allow a sponsor or
applicant to provide a brief statement of the reason for not conducting
the investigation in accordance with GCP and to describe the steps
taken to ensure that the data and results are credible and accurate and
that the rights, safety, and well-being of human subjects have been
adequately protected.
    FDA has also added a waiver provision as an alternative option that
allows sponsors and applicants to request a waiver from any applicable
requirement under Sec.  812.28(a)(1) and (b). (See Sec.  812.28(c).)
The request must provide an explanation of why the sponsor's or
applicant's compliance with the requirement is unnecessary or cannot be
achieved; a description of an

alternative submission or course of action that satisfies the purpose
of the requirement; or other information justifying a waiver.
    Through these mechanisms, sponsors and applicants can provide
information for FDA's consideration in deciding whether to accept, on a
case-by-case basis, data from a clinical investigation that is not
conducted in accordance with GCP or for which the sponsor or applicant
does not have information on how the investigation was conducted.
    (Comment 12) Two comments noted that sponsors and applicants may
not be able to conduct all studies according to GCP due to requirements
in the country where the study is conducted. The comments noted that in
at least one country, ethics committees will not review post-market on-
label studies because their scope is limited to investigational studies
even though such studies may be submitted in support of applications
and submissions to FDA.
    (Response) FDA agrees that there may be situations where full
conformity with GCP may be difficult or not feasible. FDA believes that
conducting a clinical investigation in accordance with GCP will help to
ensure that the data and results are credible and accurate and that the
rights, safety, and well-being of human subjects are adequately
protected. If the sponsor or applicant cannot meet GCP for the
investigation, the sponsor or applicant may provide an explanation of
the departure from GCP or request a waiver, as noted previously. FDA
will take this information into account when considering the extent to
which the Agency can rely on the data from these investigations on a
case-by-case basis.

D. In Vitro Diagnostic (IVD) Devices

    (Comment 13) Several comments recommended that FDA exempt from the
informed consent provisions IVD studies conducted with de-identified
samples consistent with FDA's ``Guidance on Informed Consent for In
Vitro Diagnostic Device Studies Using Leftover Human Specimens that are
Not Individually Identifiable.'' The comments state that application of
GCP in this context would provide no additional protection and could
deter innovation. One comment suggested that the concepts in the
guidance be codified in the final rule.
    (Response) The ``Guidance on Informed Consent for In Vitro
Diagnostic Device Studies Using Leftover Human Specimens that are Not
Individually Identifiable'' does not exempt any clinical investigations
from the informed consent requirements. In that guidance, FDA stated
that we intend to exercise enforcement discretion with regard to the
requirement for informed consent under the circumstances described in
section 4 of the guidance. FDA issued the guidance to address concerns
about obstacles to the development of IVDs and to facilitate
development in a manner consistent with the principles of good clinical
practice, including human subject protection. In addition to sponsors
being able to apply the guidance to certain IVD investigations
conducted in the United States, FDA does not intend to object if
sponsors and applicants follow this guidance for similar IVD
investigations conducted outside the United States provided there is no
conflict with local laws and regulations.
    The 21st Century Cures Act (Cures Act) (Pub. L. 114-255) was
enacted on December 13, 2016. Title III, section 3023 of the Cures Act
requires the Secretary of Health and Human Services (HHS), to the
extent practicable and consistent with other statutory provisions, to
harmonize the differences between the HHS human subject regulations and
FDA's human subject regulations. FDA will be working with others at HHS
in carrying out this statutory directive, including with respect to de-
identified human specimens.
    (Comment 14) Three comments indicated that the rule should not
apply to technical and analytical (or bench) studies that support IVD
devices, especially when de-identified leftover specimens are used. Two
comments indicated that these studies are subject to Good Laboratory
Practices regulations and are conducted with IRB oversight and informed
consent except under the circumstances described in the FDA's
``Guidance on Informed Consent for In Vitro Diagnostic Device Studies
Using Leftover Human Specimens that are Not Individually
Identifiable.'' These comments stated that application of GCP would
provide no additional protection and would slow or deter innovation.
    (Response) FDA disagrees with these comments. FDA considers
investigations that use human specimens, including leftover specimens
that are de-identified, to be clinical investigations. The definition
of subject in Sec.  812.3(p) includes individuals on whose specimens an
investigational device is used. Data from investigations using human
specimens are subject to the GCP rule when submitted to FDA in support
of an IDE or a device marketing application or submission. FDA
disagrees that the application of GCP would provide no additional
protection. The application of GCP helps to ensure the quality and
integrity of data from investigations using human specimens. We agree
that these investigations should be conducted with IEC oversight and
informed consent. However, as stated previously, in addition to
sponsors being able to apply the ``Guidance on Informed Consent for In
Vitro Diagnostic Device Studies Using Leftover Human Specimens that are
Not Individually Identifiable'' to certain IVD investigations conducted
in the United States, FDA does not intend to object to sponsors and
applicants following the guidance for similar IVD investigations
conducted outside the United States, provided that there is no conflict
with local laws and regulations.
    As noted above, investigations using human specimens are considered
clinical investigations. The Good Laboratory Practices regulation (part
58 (21 CFR part 58)) does not apply to clinical investigations,
including investigations using human specimens. Further explanation of
the applicability of part 58 is provided in FDA's ``Guidance for
Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies--
Frequently Asked Questions.''
    (Comment 15) One comment noted that there is no harmonized,
international IVD GCP guideline.
    (Response) FDA recognizes that the ISO 14155:2011 standard states
that it does not apply to IVD medical devices. FDA, however, considers
conformity with the principles of GCP important for all clinical
investigations, including those of IVD devices, to help ensure that the
data and results from clinical investigations are credible and accurate
and that the rights, safety, and well-being of human subjects are
adequately protected. As stated above, FDA does not intend to object to
sponsors and applicants following the ``Guidance on Informed Consent
for In Vitro Diagnostic Device Studies Using Leftover Human Specimens
that are Not Individually Identifiable,'' provided that there is no
conflict with local laws and regulations.
    (Comment 16) One comment noted that the United States classifies
IVDs as medical devices but other countries, for example, countries
within the European Union, have separate directives governing medical
devices and IVDs. Additionally, the Global Harmonization Task Force
guidance documents on Clinical Evidence for IVD Medical Devices
differentiate IVDs from other medical devices and the proposed
regulations do not reflect these differences.

    (Response) FDA agrees that there are differences in how other
countries regulate medical devices and IVDs. The rule, however, does
not address when evidence obtained from using human specimens is needed
or what clinical evidence is required for a medical device, including
an IVD. Instead, the rule only addresses the conditions for FDA
acceptance of data from clinical investigations to support an IDE or a
device marketing application or submission to FDA, including data from
clinical investigations conducted outside the United States. Conformity
with GCP helps to ensure that the data and results are credible and
accurate and that the rights, safety, and well-being of human subjects
are adequately protected. This is equally important for investigations
of IVDs as it is for other medical devices. FDA believes the rule
allows for the flexibility needed to accommodate the rules and
regulations of other countries.

E. Independent Ethics Committee

    Proposed Sec.  812.3(t) would add a definition for IEC. We proposed
to define IEC to mean 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.
    (Comment 17) Three comments were concerned with the use of the term
``adequately constituted'' in the definition of IEC because the term is
not defined. One comment noted that a global, harmonized definition of
``adequately constituted'' does not exist, nor is there agreement on
the makeup of an IEC. Another comment recommended that existing
definitions of IEC, such as in ICH E6 and ISO 14155:2011, be used.
    (Response) FDA disagrees with the comments. The proposed definition
of IEC is at a level of specificity and detail appropriate for
regulation. We recognize that the organization and membership of IECs
may differ among countries because of the local needs of the host
country. We believe that such variation should not affect an IEC's
ability to perform its functions of protecting the rights, safety, and
well-being of human subjects involved in the clinical investigation.
Further, we intended for the rule to be sufficiently flexible to
accommodate differences in how countries regulate the conduct of
clinical research, including the composition of an IEC. Therefore, we
have not specifically defined IEC membership requirements in the
regulations.
    Although we have not identified specific requirements for the
membership of an IEC in the rule, we note that the definition of an IEC
references an IRB subject to the requirements of part 56 as one type of
IEC. Another example would be the description provided in ICH E6.

F. Acceptance of Data From Clinical Investigations Conducted Outside
the United States

    Proposed Sec.  812.28(a) would identify requirements for the
acceptance of information from clinical investigations conducted
outside the United States as support for an IDE or a device marketing
application or submission, including a requirement that a statement be
provided that the investigation was conducted in accordance with GCP,
which we defined in Sec.  812.28(a)(1).
    (Comment 18) One comment questioned whether there are data to
support concern with data integrity and human subject protection from
studies of medical devices conducted outside the United States, similar
to the Office of Inspector General (OIG) June 2010 report, ``Challenges
to FDA's Ability to Monitor and Inspect Foreign Clinical Trials,'' for
drug and biological product marketing applications (see https://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf).
    (Response) FDA notes that there is no similar OIG report for
devices, but FDA does have experience with investigations conducted
outside the United States through the foreign sites we have inspected.
From this experience, we are aware of instances of misconduct of
clinical investigations that could compromise data integrity and human
subject protection. For more information, please see our Bioresearch
Monitoring (BIMO) Metrics available at https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm261409.htm.
    (Comment 19) One comment noted that proposed Sec.  812.28(a)(1)
defines GCP to include ``obtaining and documenting the freely given
informed consent of the subject . . . before initiating a study'' and
suggested we change the sentence to ``obtaining and documenting the
freely given informed consent of the subject before that subject
participates in the study'' because subjects will enroll in a clinical
study throughout the enrollment phase of a study, so stating that
informed consent will be obtained from a subject before initiating a
study is not realistic.
    (Response) FDA declines to make this change to the definition of
GCP in Sec.  812.28(a)(1) because the definition is consistent with the
definition in Sec.  312.120(a)(1)(i). The intention of the sentence is
that informed consent is obtained before initiating the subject's
participation in the study.
    (Comment 20) One comment suggested adding to the end of proposed
812.28(a)(1): ``For the purpose of definition, device GCP does not
include a requirement for sponsor collection and analysis of (i)
adverse events beyond those specified in the protocol and those that
would meet the definition of a UADE, (ii) concomitant medications and
concomitant therapies beyond those specified in the protocol, (iii) any
other data not specifically required of clinical investigations
conducted under an IDE or not specified in the protocol.'' The change
is intended to clarify that the requirements for a drug clinical study
are not being systematically required for medical device studies
conducted outside the United States.
    (Response) FDA disagrees with the suggested change. FDA has written
the rule to be flexible to accommodate the laws and regulations of the
countries where investigations are conducted. FDA expects that clinical
investigations will be conducted in compliance with the local laws and
regulations of the countries where the investigations take place and
such laws and regulations may address collection and analysis of
adverse events, concomitant medications and therapies, and other data.
FDA considers the suggested language too restrictive because, during
the course of an investigation, additional data may be collected that
would be important to establishing the safety and effectiveness of a
medical device or to subject safety. Moreover, the suggested language
relies on FDA's investigational device exemptions regulations by using
a term (unanticipated adverse device effect or UADE) used in FDA's
regulations and limits ``collection and analysis'' by not requiring
``any other data not specifically required of clinical investigations
conducted under an IDE or not specified in the protocol.'' These
changes would modify the definition of GCP based on FDA's regulations
and it may appear that FDA is imposing its own GCP regulations on other
countries. Additionally, the revisions could raise problems for
investigations of combination products.
    Adverse event reporting is an important aspect of GCP. The
requirements related to collection and analysis of adverse events would
be those identified in the GCP standard the sponsor uses. For example,
ISO 14155:2011 includes discussion of adverse event documentation,
reporting, and analysis in several sections,

including sections 6.4, 8.2.4, 8.2.5, and 9.8. A sponsor could request
a waiver from any applicable requirement if the sponsor can justify why
it is unnecessary, cannot be achieved, or can be satisfied through an
alternative course of action.
    (Comment 21) One comment noted that the text in proposed Sec.
812.28(a) uses the term ``data are valid'' but stated this term is
vague and recommends changing it to ``relevant and credible.''
    (Response) FDA agrees that the language in proposed Sec.  812.28(a)
regarding ``data are valid'' should be revised but disagrees with the
suggested revision. The term ``data are valid'' was used in previous
Sec.  814.15(b) to indicate the data must represent valid scientific
evidence, which is appropriate for PMA applications. Section 812.28,
however, addresses data supporting other applications and submissions,
including clinical data supporting an IDE application. Therefore, we
have revised Sec.  812.28(a) to read ``FDA will accept information on
clinical investigations conducted outside the United States to support
an IDE or a device marketing application or submission if the
investigations are well-designed and well-conducted . . .'' consistent
with Sec.  312.120, which similarly applies to investigational
applications in addition to marketing applications for drugs and
biological products.
    (Comment 22) One comment stated that phrases like ``compliance with
good clinical practice'' might lead the reader to interpret FDA as
expecting compliance with ICH E6 versus the phrase ``compliance with
the principles of good clinical practice,'' which more readily relates
to the concepts described in ISO 14155:2011.
    (Response) FDA disagrees with this comment. Both ICH E6 and ISO
14155:2011 use the term ``principles of good clinical practice.'' FDA
did use the term ``principles of good clinical practice'' in proposed
Sec.  812.2(e); however, we have removed this proposed section from the
final rule to eliminate potential misinterpretation that part 812
applies to clinical investigations conducted outside the United States.
Section 812.28(a)(1) uses the phrase ``conducted in accordance with
good clinical practice.'' This section defines GCP and requires a
sponsor or applicant to provide a statement regarding the conduct of
the investigation submitted. The sponsor or applicant would indicate
conformity with a specific GCP standard but the rule does not specify
the GCP standard to use. Therefore, FDA believes the language in the
rule is appropriate in the context in which it is used.
    (Comment 23) One comment asked whether the Agency looked at the
differences between ICH E6 and ISO 14155:2011, related to device
stakeholders' requirements, to identify if there are any differences
and considered the potential burden to adopt both standards.
    (Response) FDA has not identified a specific GCP standard that
sponsors must follow. Instead, FDA is allowing sponsors of device
clinical investigations conducted outside the United States to follow a
GCP standard of their choice, provided it meets the definition provided
in Sec.  812.28(a)(1). Although FDA believes that ICH E6 and ISO
14155:2011 represent similar approaches to GCP, we note that ICH E6
addresses drug and biological products, while ISO 14155:2011 addresses
medical devices. We believe the differences are appropriate to the
different products addressed.

G. Onsite Inspection

    Proposed Sec.  812.28(a)(2), as a condition for acceptance of data
from a clinical investigation submitted under this section, would
require a statement assuring the availability of the data from the
clinical investigation to FDA for validation through an onsite
inspection if the Agency deems it necessary or through other
appropriate means.
    (Comment 24) One comment stated that FDA has no authority to
inspect foreign clinical study institutions and recommended that
proposed Sec.  812.28(a)(2) be struck. Another comment indicated that
providing a statement as required by proposed Sec.  812.28(a)(2) would
be problematic because of foreign privacy laws.
    (Response) FDA disagrees with striking proposed Sec.  812.28(a)(2),
now Sec.  812.28(a)(3), because, in some cases (for example, to resolve
any uncertainties about whether the investigation was conducted in
accordance with GCP), to accept the data from a clinical investigation
conducted outside the United States, FDA may need to validate the data
through an onsite inspection. Historically, when needed to validate
data from clinical investigations conducted outside the United States,
FDA has been able to inspect the records of these investigations. When
conducting foreign inspections, FDA obtains the consent of foreign
governments.
    FDA understands that a sponsor cannot disclose foreign records that
are prohibited from disclosure by foreign law. If the Agency believes
that access to records is necessary to verify certain data or to
validate the investigation, and such records are not available because
of foreign law, the sponsor and FDA will need to agree upon an
alternative means for validation if the Agency is to rely on the data.
Such alternative means for validation might entail FDA partnering with
other regulatory authorities or other mutually agreed upon means for
validation.
    (Comment 25) One comment recommended keeping the language the same
as in Sec.  312.120(a)(1)(ii): That is, ``FDA is able to validate the
data from the study through an onsite inspection if the agency deems it
necessary.'' Another comment recommended modifying the language to
``authorized by local law'' and deleting ``or through other appropriate
means'' unless FDA can clarify what it means and what types of
activities would satisfy this requirement.
    (Response) FDA partially agrees and has modified the language in
proposed Sec.  812.28(a)(2), now Sec.  812.28(a)(3), to more closely
follow the language in Sec.  312.120. We have modified the requirement
that a statement be provided assuring the availability of the data from
the study to FDA for validation through an onsite inspection to a
requirement that FDA is able to validate the data from the
investigation through an onsite inspection. We have also determined
that the phrase ``if otherwise authorized by law'' is unnecessary
because FDA obtains the consent of foreign governments to do
inspections. Therefore, the phrase has been deleted.
    We are keeping the phrase ``or through other appropriate means.''
Essentially the same phrase is used in current Sec.  814.15(d)(3)
regarding validation of foreign clinical data. This language recognizes
that foreign data present unique challenges not usually associated with
domestic data. One such challenge may be that FDA is unable to conduct
an onsite inspection. If the Agency believes that validation is
necessary but is unable to conduct an onsite inspection, the sponsor
and FDA will need to agree upon an alternative means for validation if
the Agency is to rely on the data. Such alternative means for
validation might entail FDA partnering with other regulatory
authorities or other mutually agreed upon means for validation. If an
agreement cannot be reached that satisfies FDA's need for validation,
then the data might not be accepted to support the application or
submission.
    (Comment 26) One comment noted that the preamble of the proposed
rule identified documents that articulate GCP principles but that these
documents have broad differences in the

scope, level of detail, and formulation of actual requirements and that
no individual document was identified as the authoritative set of
enforceable requirements. The comment stated that, if GCP compliance
will be subject to FDA inspection, the rule must clearly identify not
only the applicable requirements in terms of general principles but
also provide a sufficient level of detail to allow an objective basis
for a uniform assessment of compliance by the sponsor as well as the
Agency.
    (Response) FDA disagrees with this comment. Similar to Sec.
312.120, the rule does not identify a specific GCP standard that
sponsors must follow. Instead, the rule includes a definition of GCP in
Sec.  812.28(a)(1), which is consistent with the definition in Sec.
312.120, and embodies well recognized GCP principles. FDA is allowing
sponsors of clinical investigations conducted outside the United States
to follow a GCP standard of their choice, provided it meets the
definition provided in Sec.  812.28(a)(1). One example of a GCP
standard that meets the definition provided in Sec.  812.28(a)(1) is
ISO 14155:2011, ``Clinical Investigation of Medical Devices for Human
Subjects--Good Clinical Practice.'' FDA has recognized this standard
(77 FR 15765). In addition to following a GCP standard, sponsors would
need to comply with the local requirements where the investigational
sites are located.

H. Supporting Information

    Proposed Sec.  812.28(b) would require a sponsor or applicant
submitting data from clinical investigations conducted outside the
United States in support of an IDE or device marketing application or
submission to submit, in addition to information required elsewhere in
parts 807, 812, and 814, supporting information that describes the
actions taken to ensure that the research conformed to GCP.
1. General Comments
    (Comment 27) One comment stated that the list of supporting
information in Sec.  812.28(b) should reflect the approval standard for
devices, which is a reasonable assurance of safety and effectiveness.
    (Response) FDA disagrees with the comment. The supporting
information is not used to establish a reasonable assurance of safety
and effectiveness. Instead, the supporting information is used to
assess whether the investigation conformed to GCP, which helps to
ensure that the data and results submitted are credible and accurate
and that the rights, safety, and well-being of human subjects are
adequately protected. Data from clinical investigations conducted in
accordance with GCP may be used to establish a reasonable assurance of
safety and effectiveness for purposes of a PMA application, but may
also be used to support other device applications and submissions,
including an IDE. Section 812.28(a)(2) of the rule identifies different
supporting information requirements based on the level of risk of the
clinical investigation, with significant risk device investigations
requiring more supporting information and device investigations
presenting less risk, as well as those that meet the exemption criteria
in Sec.  812.2(c), requiring less supporting information.
    (Comment 28) One comment noted that the preamble to the proposed
rule states that many of the requirements in Sec.  812.28(b) parallel
the requirements in Sec.  312.120(b) for drug applications but the
list, in many cases, is more restrictive than the requirements for drug
studies, and identified the request for certified copies in Sec.
812.28(b)(4) as an example.
    (Response) FDA, in general, disagrees with the comment. Although
the comment indicates that the list of supporting information in Sec.
812.28(b) is more restrictive in many cases than in Sec.  312.120(b),
only one example is provided, the request for ``certified copies'' in
Sec.  812.28(b)(4). Based on concerns raised by this and other similar
comments, we have removed the term ``certified copies'' from Sec.
812.28(b)(4), as further discussed in response to comment 33 below.
    There are only a few other differences between Sec. Sec.  812.28(b)
and 312.120(b). In Sec.  312.120(b)(1) and (2), the investigator's
qualifications and a description of the research facilities are
required, respectively. In Sec.  812.28(b)(1), we require the names of
investigators and the names and addresses of research facilities and
sites where records relating to the investigation are maintained,
separate from the requirement for the investigators' qualifications in
Sec.  812.28(b)(2) and the description of the research facilities in
Sec.  812.28(b)(3). We believe this difference is appropriate because
the information on names of investigators and names and addresses of
research facilities and sites where records relating to the
investigation are maintained is needed for all clinical investigations
of medical devices. However, the information on investigators'
qualifications and the description of the research facilities is needed
for significant risk device investigations but not for exempt and non-
significant risk device investigations. These items are discussed
further in comments 29 and 30 below.
    The required information in Sec.  812.28(b)(5), describing the
device used in the investigation, is also different from Sec.
312.120(b)(4), describing the drug substance and drug product. The
difference is appropriate because it relates to the differences in
information needed to adequately describe devices and drugs.
    The difference between Sec. Sec.  812.28(b)(6) and 312.120(b)(5) is
related to different regulatory requirements for FDA decisions on
device applications, as described in Sec.  860.7 (21 CFR 860.7), and
drug applications, as described in Sec.  314.126. Therefore, FDA
believes this difference is appropriate.
    The last difference concerns the information required for the IEC
that reviewed the investigation. In Sec.  812.28(b)(7), we do not
specify that records of the IEC members' names be maintained as
required in Sec.  312.120(b)(6). We decided not to require that records
of the IEC members' names be maintained because drug sponsors and
applicants reported occasional problems fulfilling this requirement due
to foreign laws.
    Therefore, FDA considers the supporting information identified in
Sec.  812.28(b) to be similar to the supporting information required
for drug applications in Sec.  312.120(b), with the few differences
being appropriate and not more restrictive.
2. Investigators and Research Facilities
    Proposed Sec.  812.28(b)(1) would require the names and addresses
of the investigators and research facilities; proposed Sec.
812.28(b)(2) would require the qualifications of investigators; and
proposed Sec.  812.28(b)(3) would require a description of the research
facilities.
    (Comment 29) One comment disagreed with providing investigators'
addresses and noted that personal details like this are not usually
obtained and could be subject to more stringent foreign regulations. A
second comment stated that the European Union Privacy Directive would
protect from transfer to the United States the names and addresses of
foreign investigators and that investigators would have to agree to
this information sharing in advance or at the time of submission to
FDA. The comment further stated that difficulties currently exist with
obtaining investigators' names from certain foreign sites, even when
the data collection is part of an IDE.

    (Response) FDA believes that some clarification is needed but
disagrees that investigators' names should not be required. We did not
intend to imply that investigators' personal addresses would be
required. We have reworded this element to require ``names of
investigators and names and addresses of research facilities and sites
where records relating to the investigation are maintained.'' This
change clarifies that the investigators' personal addresses are not
required, but that the names and addresses of all facilities that took
part in the investigation are required, such as the investigational
sites, laboratories, and specimen collection sites. Additionally, if
study records are maintained at other locations, such as an
investigator's office, the names and addresses of those locations must
also be provided.
    We also note that the European Commission has recognized ISO
14155:2011, which includes providing names and addresses of
investigators to regulatory authorities. ISO 14155:2011, Annex A,
describes the clinical investigation plan (CIP) and includes, in
section A.1.4, the name, addresses, and professional position of
principal investigator(s). The CIP is included in the clinical
investigation report as described in section D.13 of Annex D. The
clinical investigation report includes ``the list of principal
investigators and their affiliated investigation sites, including a
summary of their qualifications or a copy of their CVs'' (see Annex
D.13 c). This report is provided to regulatory authorities per section
7.3f.
    (Comment 30) One comment stated that the items in Sec.
812.28(b)(2) and (3) are vague and sponsors or applicants will have
difficulty knowing how to comply with the requirements.
    (Response) In general, the information provided on investigator
qualifications should be adequate to show that the investigator is
qualified to serve as an investigator based on his or her training and
experience specifically related to the clinical investigation (for
example, such information could include a curriculum vitae (CV) or
summary of training and experience). The description of the research
facilities should include enough information to enable FDA to determine
the adequacy of the facilities to execute the investigation and meet
its requirements (for example, whether the site is appropriately
staffed and equipped to conduct the investigation and is able to
provide the appropriate emergent or specialized care, if required).
Additionally, the GCP standard the sponsor or applicant follows may
address information to maintain on investigator and research facility
selection. For example, ISO 14155:2011 addresses verification and
documentation of the qualifications of the principal investigator(s)
and the adequacy of the research facility and the rationale for
selecting the facility in sections 5.8, 9.2, and 9.3.
    The investigator's qualifications and the description of the
research facilities will also help us to assess the need for an onsite
inspection.
3. Detailed Summary of Protocol and Results of Investigation
    Proposed Sec.  812.28(b)(4) would require submission of a detailed
summary of the protocol and results of the investigation. In addition,
the sponsor or applicant would be required to submit certified copies
of case records maintained by the investigator or additional background
data, such as hospital records or other institutional records, if
requested by FDA.
    (Comment 31) Several comments stated that stricter privacy laws
outside the United States may partially or completely restrict the
ability of sponsors and applicants to provide copies of patient records
to FDA. The comments noted that investigational sites typically archive
the originals of completed case records and these records would
generally not be available to sponsors. Two comments noted that the
records may be available through an inspection at the investigational
site. One comment noted that providing redacted patient information to
a regulatory authority may be possible but would require changes to
clinical trial agreements and informed consent documents and would
impose significant burden and costs. Comments recommended modifying or
deleting the requirement for providing records.
    (Response) FDA acknowledges that in some instances there may be
difficulties providing records should FDA request them but disagrees
with deleting the requirement. FDA understands that a sponsor cannot
disclose foreign records that are prohibited from disclosure by foreign
law. If FDA requests case records or other records but these documents
cannot be provided as required by Sec.  812.28(b)(4) because disclosure
is prohibited by governing law, the sponsor or applicant should
document this disclosure prohibition by the foreign entity. For
example, the sponsor or applicant should document the countries that
prohibit such disclosure, the nature of the prohibitions, and the
extent to which these prohibitions may impede sponsors or applicants in
carrying out other obligations regarding record access. The sponsor or
applicant can then submit such information in a waiver request to FDA.
For FDA to rely on the affected data, the sponsor or applicant and FDA
would need to agree on an alternative means for validation. Such
alternative means for validation might entail FDA partnering with other
regulatory authorities or other mutually agreed upon means for
validation.
    Additionally, in the informed consent documents, it may be helpful
to notify subjects that regulatory authorities will have direct access
to the subject's medical records for verification of clinical
investigation procedures and data, which is consistent with ISO
14155:2011, section 4.7.4(d)3.
    If FDA needs source documents such as hospital records to verify
certain data or to validate the investigation and such records are not
available because of foreign law, and an alternative means for
validation is not available, FDA might not accept the data from the
clinical investigation as support for an IDE or device marketing
application or submission.
    (Comment 32) Two comments requested clarification of the term
``case record.''
    (Response) FDA clarifies that the term ``case record'' as used in
Sec.  812.28(b)(4) is used to indicate records investigational sites
commonly maintain in relation to clinical investigations. The term
includes records as described in Sec.  812.140(a)(3).
    (Comment 33) Two comments requested that the term ``certified
copies'' be defined.
    (Response) FDA has reevaluated the provision related to ``certified
copies.'' We acknowledge that the term has different meanings in other
countries and have determined that this term is not needed. We have
amended the rule accordingly.
    (Comment 34) One comment recommended modifying Sec.  812.28(b)(4)
to require that the clinical investigation report, as described in ISO
14155:2011 Annex D, be included in the supporting information because
it provides the relevant information from the protocol as well as the
results of the clinical investigation.
    (Response) FDA disagrees with modifying the requirement to specify
providing the clinical investigation report as described in ISO
14155:2011. We believe that the supporting information required by the
rule is sufficient for its purpose. Additionally, the rule does not
require following ISO 14155:2011; however, if a sponsor or applicant
chooses, FDA would accept the full clinical investigation report as

described in Annex D of ISO 14155:2011 as a detailed summary of the
protocol and results of the investigation.
    (Comment 35) One comment asked about FDA's procedure and methods
for review, retention, and destruction of the detailed summaries and
records identified in Sec.  812.28(b)(4) and the reasons why records
would be needed and the intent of review.
    (Response) FDA may request records to help understand the conduct
of the investigation, to verify certain data, and to validate the
investigation and the results obtained. When records from
investigations conducted outside the United States are submitted, FDA
will review and handle those records in the same manner as records from
investigations conducted in the United States.
4. Valid Scientific Evidence
    Proposed Sec.  812.28(b)(6) would require a discussion
demonstrating that the data and information, when intended to support
the safety and effectiveness of a device, constitute valid scientific
evidence.
    (Comment 36) One comment stated that Sec.  812.28(b)(6) is
redundant and should be struck. A study complying with the principles
of GCP is a well-controlled study conducted by qualified experts.
    (Response) FDA disagrees that Sec.  812.28(b)(6) is redundant.
Section 812.28(b)(6) requires that the sponsor or applicant provide a
discussion demonstrating that the data and information constitute valid
scientific evidence within the meaning of Sec.  860.7. FDA relies upon
only valid scientific evidence to determine whether there is reasonable
assurance that the device is safe and effective (see Sec.  860.7).
Although there may be some overlap, the principles addressing valid
scientific evidence more readily relate to the types of evidence that
may support the safety and effectiveness of a device, while the
principles of GCP relate more to the conduct of the investigation.
5. IEC Information
    Proposed Sec.  812.28(b)(7) would require 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 would be
required to maintain records supporting such statement, including
records describing the qualifications of IEC members, and would be
required to make these records available for Agency review upon
request.
    (Comment 37) Two comments opposed the requirement that a statement
be provided that the IEC meets the definition in Sec.  812.3(t). One
comment indicated that sponsors may not know whether an IEC meets a
given definition. Another comment recommended requiring a statement
obtained from the IEC that it meets the definition in Sec.  812.3(t)
and is organized and operates according to applicable laws and
regulations.
    (Response) FDA agrees that a statement from the IEC would also be
acceptable. To satisfy this requirement, FDA will accept a statement
from the IEC indicating it meets the definition of an IEC in the rule.
We also added a waiver provision (see new Sec.  812.28(c)) to the rule
that sponsors and applicants may consider using when they are unable to
meet the requirements in Sec.  812.28(a)(1) and (b) of the rule. For
example, a waiver may be requested when the sponsor cannot submit a
statement that the IEC meets the definition in Sec.  812.3(t). A waiver
request could identify, as an alternative to the statement that the IEC
meets the definition in Sec.  812.3(t), a statement that the IEC is
organized and operates according to the applicable laws and regulations
of the country where it operates and provide a description of the laws
and regulations under which the IEC is organized and operates. FDA will
decide whether to grant or deny a waiver on a case-by-case basis,
taking into account all appropriate circumstances.
    (Comment 38) Three comments stated that the proposed rule requires
sponsors to qualify IECs but there is no parallel requirement for a
sponsor to qualify an IRB for a study in the United States. One comment
noted that no rationale was provided for requiring greater regulation
outside the United States than is required in the United States.
Another comment indicated the requirement is likely because FDA
recognized it does not have the authority to verify and document the
adequacy of a foreign IEC but failed to recognize that sponsors do not
have such authority and would face legal challenges to meet this
requirement.
    (Response) FDA acknowledges that the sponsor of an investigation
under an IDE is not required to qualify and submit information on the
adequacy of the reviewing IRBs. FDA routinely obtains information about
IRBs in the United States through onsite inspections of the IRBs. To
obtain information on the adequacy of the reviewing IEC for foreign
investigations, given that inspections of foreign IECs are usually not
feasible, FDA believes it is appropriate to ask the sponsor to document
the adequacy of the reviewing IEC because the sponsor already interacts
with the IEC, either directly or through the investigators, to obtain
IEC review.
    FDA believes that the oversight of a clinical investigation by an
adequately constituted IEC is an essential component of human subject
protection. Information about the adequacy of an IEC is important in
assessing the competence of the committee to protect the rights,
safety, and well-being of human subjects. To satisfy this requirement,
FDA will accept a statement from the IEC indicating it meets the
definition of an IEC in the rule. We also added a waiver provision to
the rule that sponsors and applicants may consider using when they are
unable to meet the requirements in Sec.  812.28(a)(1) and (b) of the
rule. For example, a waiver may be requested when the sponsor cannot
submit a statement that the IEC meets the definition in Sec.  812.3(t).
    (Comment 39) Several comments indicated sponsors may have
difficulty obtaining and documenting the qualifications of IEC members
and making the records available to the Agency upon request. One
comment noted that the term ``qualification'' is open to
interpretation. Another comment indicated it may not be feasible to
obtain the names of IEC members. A third comment noted that the
European Union Privacy Directive may protect from transfer to the
United States the information sought for the IEC.
    (Response) FDA believes that oversight of a clinical investigation
by an adequately constituted IEC is an essential component of human
subject protection. Information about the adequacy of an IEC is
important in assessing the competence of the committee to protect the
rights, safety, and well-being of human subjects. Recognizing that
privacy laws in some countries may not allow the release of personal
information, FDA is requiring that sponsors or applicants maintain
records describing the qualifications of IEC members and not their
names. Qualifications would include, for example, information on
occupation, training, and experience.
    Additionally, we have added a waiver provision to the rule that
sponsors and applicants may consider using when they are unable to meet
the requirements in Sec.  812.28(a)(1) and (b) of the rule. If sponsors
or applicants cannot obtain IEC member qualifications as required by
Sec.  812.28(b)(7), FDA recommends that

the sponsor or applicant clearly document attempts made to obtain the
qualifications of IEC members along with an explanation as to why the
qualifications cannot be obtained. Such information can be submitted to
FDA in a waiver request.
    (Comment 40) One comment questioned how FDA would review
information on the qualifications of IEC members stating that, without
a harmonized, globally accepted definition of ``qualification,'' there
will be variability in interpretation of acceptable qualification based
on reviewer interpretation or bias and may place FDA in the position of
accepting or rejecting qualifications of IEC members from foreign
nations.
    (Response) FDA disagrees with the comment. We recognize that the
membership of IECs may differ among countries because of local needs of
the host country. Such variation is acceptable as long as the IEC can
ensure the protection of the rights, safety, and well-being of human
subjects involved in the clinical investigation. As we do for IRBs
located in the United States, in its review FDA will be looking to see
that, collectively, the IEC members have the qualifications needed to
review and evaluate the science, medical aspects, and ethics of the
proposed clinical investigation.
6. Summary of IEC's Decision
    Proposed Sec.  812.28(b)(8) would require submission of a summary
of the IEC's decision to approve or modify and approve the study, or to
provide a favorable opinion.
    (Comment 41) One comment recommended changing proposed Sec.
812.28(b)(8) to require the correspondence relating to the IEC's
decision to approve the investigation because the approval letter would
be clearer and less ambiguous than a summary, which could be
interpreted differently by different people.
    (Response) FDA disagrees with the comment; however, FDA believes
that providing the approval letter(s) from the IEC(s) would be one way
to provide a summary of the IEC's decision to approve or provide a
favorable opinion. We note that these letters are usually issued in the
local language of the country in which the investigation is conducted
and official translations may need to be provided.
7. Description of Informed Consent Process
    Proposed Sec.  812.28(b)(9) would require submission of a
description of how informed consent was obtained.
    (Comment 42) One comment recommended that Sec.  812.28(b)(9)
require that the blank informed consent document approved by the IEC or
IRB be submitted instead of a ``description of how'' consent was
obtained.
    (Response) FDA disagrees that the blank informed consent document
approved by each IEC or IRB should be submitted instead of a
description of how consent was obtained. Providing information about
how informed consent is obtained is important in ensuring transparency
and accountability for the ethical conduct of the investigation. The
description should address such concerns as who obtained informed
consent (ensuring that the person obtaining informed consent was
knowledgeable about the investigation and capable of answering all
questions), when was consent obtained (ensuring that consent was
obtained prior to a subject's participation in the investigation, for
example, prior to any research procedures), and the conditions under
which consent was obtained (ensuring that consent was obtained under
conditions that minimized coercion or undue influence).
    (Comment 43) One comment recommended revising Sec.  812.28(b)(9) to
state ``a description of how informed consent was obtained, and that
this method was approved by the IEC.''
    (Response) FDA disagrees with the comment. FDA defines GCP to
include the review and approval (or provision of a favorable opinion)
by an IEC that is responsible for ensuring the protection of the
rights, safety, and well-being of human subjects involved in a clinical
investigation. Ensuring the protection of human subjects would include
review and approval of how informed consent is obtained. An applicant's
statement that an investigation was conducted in accordance with GCP
would indicate that an IEC had approved (or provided a favorable
opinion) of how informed consent was obtained. Therefore, FDA believes
the proposed revision is unnecessary.
8. Description of Incentives to Subjects
    Proposed Sec.  812.28(b)(10) would require submission of a
description of what incentives, if any, were provided to subjects to
participate in the study.
    (Comment 44) One comment recommended deleting Sec.  812.28(b)(10)
because this is a new requirement, not required for investigations in
the United States, and may lead to unnecessary burden of review for
FDA. The comment stated that the information is reviewed by the IRB or
IEC as part of consent and is held by the sponsor as part of their
records and subject to audit by the Agency.
    (Response) FDA disagrees with the comment and does not believe this
requirement will be overly burdensome. Informed consent documents
usually describe incentives and the IEC reviews this information.
Therefore, providing the description of incentives to FDA should not be
a burden. FDA will allow some flexibility in how sponsors or applicants
comply with Sec.  812.28(b)(10). If the informed consent form includes
a description of any incentives provided to subjects, a sponsor or
applicant could submit a model consent form to meet the requirement.
Alternatively, a sponsor or applicant could also satisfy the
requirement by submitting a description of any incentives provided to
subjects to participate in the investigation, or if such a description
was included elsewhere, such as in the detailed summary of the protocol
required under Sec.  812.28(b)(4), the sponsor or applicant could
reference where the description may be found to meet the requirement
under Sec.  812.28(b)(10).
    FDA is requiring this information because incentives can affect
data integrity. In the proposed rule, FDA only required the submission
of information about incentives for significant risk device
investigations. In the final rule, FDA is requiring that information
about incentives be made available upon request for non-significant
risk and exempt device investigations. FDA has made this change because
incentives could affect the integrity of all investigations.
    (Comment 45) One comment recommended revising Sec.  812.28(b)(10)
to state, ``a description of what incentives, if any, were provided to
subjects to participate in the study, and that these incentives, if
any, were approved by the IEC.''
    (Response) FDA disagrees with the comment. FDA defines GCP to
include the review and approval (or provision of a favorable opinion)
by an IEC that is responsible for ensuring the protection of the
rights, safety, and well-being of human subjects involved in a clinical
investigation. Ensuring the protection of human subjects would include
review and approval of the incentives to be provided to subjects. An
applicant's statement that an investigation was conducted in accordance
with GCP would indicate that an IEC had approved (or provided a
favorable opinion) of the incentives provided to subjects. Therefore,
FDA believes the proposed revision is unnecessary.

9. Description of Study Monitoring
    Proposed Sec.  812.28(b)(11) would require submission of a
description of how the sponsor monitored the study and ensured that the
study was carried out consistently with the study protocol.
    (Comment 46) One comment recommended including a statement
supporting a sponsor's performance of a risk assessment to determine
the approach to monitoring for sites outside the United States, as they
would for sites in the United States, because standardization may cause
more burdens (for example, resources, time, and cost) related to the
requirement to increase monitoring.
    (Response) FDA has not identified a specific GCP standard that
sponsors and applicants must follow. Instead, the rule defines GCP and
allows sponsors and applicants to determine an appropriate GCP standard
for their investigations that produce data to support device research
and marketing applications and submissions to FDA. Sponsors and
applicants may use a risk-based approach to monitoring, as described in
FDA's guidance document entitled ``Oversight of Clinical
Investigations--A Risk-Based Approach to Monitoring,'' provided it is
consistent with the laws and regulations of the countries where the
investigation takes place.
10. Description of Investigator Training and Signed Written Commitments
    Proposed Sec.  812.28(b)(12) would require submission of a
description of how investigators were trained to comply with GCP 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.
    (Comment 47) One comment recommended that Sec.  812.28(b)(12) only
require that the investigator agree to comply with the protocol and
with institutional and legal requirements. The principles of GCP do not
require the sponsor to train investigators in GCP compliance.
    (Response) FDA disagrees. Simply obtaining the investigator's
agreement to comply with the protocol and institutional and legal
requirements may not be adequate. Protocols may be complex and
additional steps may be needed to prepare investigators and to
standardize performance of the investigation. A description of the
steps taken to ensure consistent conduct of the investigation and
recording of data among investigators is needed. Such a description may
identify investigator meetings or other steps that the sponsor took to
ensure compliance with GCP and the protocol.

I. Record Retention

    Proposed Sec.  812.28(c), now Sec.  812.28(d) in the final rule,
would require a sponsor or applicant to maintain records for a clinical
investigation conducted outside the United States. If the investigation
supported an IDE, the records would be retained for 2 years after the
termination or completion of the IDE. If the investigation supported a
device marketing application or submission, the records would be
retained for 2 years after an Agency decision on that submission or
application.
    The proposed rule would amend Sec.  812.140(d) to include
humanitarian device exemption applications and premarket notification
submissions as types of applications and submissions that would require
the maintenance of IDE records.
    (Comment 48) One comment indicated that FDA should clarify in Sec.
812.28(c)(2) (now Sec.  812.28(d)(2)) that the requirement only applies
to studies sponsored by the sponsor or applicant of the submission or
application in which the data were submitted.
    (Response) FDA disagrees with the comment. The requirement to
maintain appropriate records is to ensure that FDA will be able to
validate an investigation through an onsite inspection, if necessary.
Therefore, the record retention requirement must apply to all
investigations from which clinical data are submitted to FDA in support
of an application or submission, whether or not the investigation was
sponsored by the sponsor or applicant. If a sponsor or applicant
submits data from a clinical investigation they did not sponsor, they
should obtain the commitment of the sponsor and investigators to retain
the records. If FDA needs access to the records and the records are not
available, FDA may not accept the data in support of an IDE or device
marketing application or submission.
    (Comment 49) One comment recommended that proposed Sec.  812.140(d)
be changed to read similarly to proposed Sec.  812.28(c), namely, ``The
date on which the investigation is terminated or completed or for 2
years after an agency decision on that submission or application.''
    (Response) FDA disagrees with the proposed change. As noted in the
preamble to the proposed rule, we are revising Sec.  812.140(d) to
indicate that retention requirements for IDE records apply to those
records used to support HDE applications and 510(k) submissions, as
well as the application types already listed. In the final rule, we
also clarify that the retention requirements apply to records used to
support requests for De Novo classifications. We do not intend to
further change the record retention requirements for IDEs.

J. Denial or Withdrawal of PMA

    Proposed Sec. Sec.  814.45(a)(5) and 814.46(a)(4) would allow FDA
to deny or withdraw, respectively, approval of a PMA if any clinical
investigation 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.
    (Comment 50) Several comments stated that the proposed rule should
allow denial or withdrawal of a PMA based only on those investigations
relied on for a determination of safety and effectiveness. One comment
noted that, for PMAs, reporting of all prior studies is required
despite not relying on all studies for a determination of safety and
effectiveness. Two comments indicated that denial and withdrawal of
approval should not be extended to other applications and submissions
such as IDEs and 510(k)s.
    (Response) FDA agrees that the rule should allow denial or
withdrawal of a PMA for noncompliance with GCP referenced in Sec.
814.15(a) and described in Sec.  812.28(a) with respect to those
clinical investigations conducted outside the United States that were
relied upon for a determination of the safety and effectiveness of the
device. FDA notes that the PMA regulations (see Sec.  814.20(b)(8))
require the applicant to provide, among other things, an
identification, discussion, and analysis of any other data,
information, or report relevant to an evaluation of the safety and
effectiveness of the device, known to or that should reasonably be
known to the applicant from any source, foreign or domestic, including
information derived from investigations other than those proposed in
the application and from commercial marketing experience. While this
information is required to be submitted, the applicant or sponsor may
not have been involved in the conduct of the investigation and may not
know the conditions under which the investigation was conducted (for
example, a previous developer or competitor may have been involved in
the conduct of the investigation).
    As explained elsewhere in this document, Sec.  812.28(a) requires
demonstration of conformity with GCP

when data from clinical investigations conducted outside the United
States are provided to support an IDE or a device marketing application
or submission; for example, when clinical data are submitted in a PMA
application to demonstrate a reasonable assurance of safety and
effectiveness. When clinical data from investigations are included in
applications and submissions as supplementary information and not as
support, demonstration of conformity with GCP is not required.
    FDA also notes that the rule only addresses denial and withdrawal
of approval related to PMAs and does not address denial or withdrawal
of authorization for other types of applications and submissions.
However, if FDA determines that any clinical investigation conducted
outside the United States and submitted in support of an IDE or a
device marketing application or submission was represented to have been
conducted in conformity with GCP but was not, FDA may take appropriate
action under the FD&C Act and FDA regulations.
    (Comment 51) Two comments noted data collected outside the United
States but not in compliance with the principles of GCP may
nevertheless be relevant data for determining the safety and
effectiveness of a device. One comment noted that, elsewhere in the
proposed rule, the use of non-GCP compliant studies is allowed where
appropriate justification is provided.
    (Response) As discussed in section IV.C, FDA agrees that clinical
data from investigations conducted outside the United States that were
not conducted in conformity with GCP may be relevant. FDA believes,
however, that clinical data that are submitted to support a PMA should
be credible, accurate, and ethically derived and that conducting a
clinical investigation in accordance with GCP will help to ensure the
integrity and quality of the data and the protection of subjects. If a
country's laws require less than GCP and the applicant does not or
cannot meet GCP for the investigation, the applicant may provide an
explanation of the departure from GCP or request a waiver. FDA will
take this information into account when considering the extent to which
it will rely on the data from these investigations in support of a
premarket submission or application on a case-by-case basis, depending
on whether the clinical data are credible, accurate, and ethically
derived. In such situations, when an applicant requests a waiver and
FDA grants the waiver and accepts for support of a PMA clinical data
from an investigation that was not conducted in conformity with GCP,
FDA generally will not deny or withdraw approval of the PMA under Sec.
814.45(a)(5) or Sec.  814.46(a)(4).
    (Comment 52) One comment stated that the sections on denial and
withdrawal of a PMA use the term ``unreliable'' without clarifying this
term and could make a determination of ``unreliable'' potentially
arbitrary, variable, and inconsistent.
    (Response) FDA disagrees with this comment. FDA has used the term
``unreliable'' in regulations such as in Sec. Sec.  812.119 and 312.70
regarding investigator disqualification. FDA uses the term according to
its common meaning and may consider data unreliable, for example, if
the data are fraudulent or if there was a lack of rigor in the conduct
of the investigation, such as not following the protocol.

K. Implementation

    (Comment 53) Several comments raised concerns with the
implementation of the rule and recommended that the rule not be applied
retrospectively to investigations begun prior to the effective date.
Two comments recommended that the effective date be established as 18
months after publication. The comments noted that adequate time will be
needed to allow for preparation for implementation, such as to revise
internal operating procedures, for training, for study planning, and
for negotiating and contracting with the necessary parties for future
studies conducted outside the United States that are intended to
support an application or submission to FDA. One comment recommended
that FDA allow requests for waivers of certain requirements for
investigations conducted prior to the effective date that are
technically out of compliance but did not compromise public health or
patient safety.
    (Response) FDA agrees that the rule should not be applied to
clinical investigations begun prior to the effective date. FDA is
implementing the rule for clinical investigations that enroll the first
subject on or after the effective date of the rule. FDA also agrees
that sponsors may need additional time to prepare to meet the new
requirements. Therefore, the effective date is established as 1 year
after the publication of the rule in the Federal Register to provide
additional time for sponsors and applicants to make any changes
necessary, for example, to their internal operating procedures, study
planning, etc., to incorporate the principles of GCP and compliance
with the requirements of the rule for investigations that will support
an IDE or device marketing application or submission. We believe that
this will provide adequate time for sponsors and applicants to
implement changes in their processes to accommodate the new
requirements.
    In addition, FDA has added a waiver provision to Sec.  812.28.
Under this provision, a sponsor or applicant may submit waiver requests
and FDA will decide whether to grant or deny waivers on a case-by-case
basis, taking into account all appropriate circumstances.
    For the purposes of this rule, we will consider a subject enrolled
when the subject agrees to participate in a clinical investigation as
indicated by the subject (or a subject's legally authorized
representative, if the subject is unable to provide informed consent)
signing the informed consent document(s) or participating in a clinical
investigation meeting the requirements of Sec.  50.24.
    If an investigation conducted outside the United States enrolled
the first subject prior to the rule's effective date, then the
requirements in Sec.  814.15 prior to the rule's effective date would
apply. Specifically, if data from clinical investigations conducted
outside the United States that enrolled the first subject prior to the
effective date of this rule are submitted in support a PMA application,
FDA will accept the data if the data are valid and the investigator has
conducted the studies in conformance with the ``Declaration of
Helsinki'' or the laws and regulations of the country in which the
research is conducted, whichever accords greater protection to the
human subjects. If the standards of the country are used, the applicant
shall state in detail any differences between those standards and the
``Declaration of Helsinki'' and explain why they offer greater
protection to the human subjects. (See Sec.  814.15(b).)

L. Guidance Needed

    (Comment 54) Two comments recommended that FDA develop guidance and
training on GCP and compliance with the requirements. One comment
recommended that FDA develop a guidance document similar to the one
available for investigational new drug applications (INDs), ``Guidance
for Industry and FDA Staff: Acceptance of Foreign Clinical Studies Not
Conducted Under an IND, Frequently Asked Questions,'' to provide
clarification and definitions to the regulations. Another comment
suggested that FDA develop guidance documents and training programs, or
sanction third-party training of physicians, sponsors, and IRBs on GCP
as it relates to medical devices. The training programs should

provide opportunities to eliminate misinterpretations while raising the
standard for GCPs.
    (Response) FDA agrees with some of these comments and believes our
responses to comments on the proposed rule provide clarification on
many issues. FDA intends to issue guidance that explains the
requirements of the rule in plain language and how sponsors and
applicants can comply with the requirements.
    On its website, FDA has provided materials related to GCP training
opportunities, including information about the annual GCP training
course that FDA has conducted.\1\ All of these training materials focus
on the regulations governing FDA-regulated clinical investigations. In
addition, FDA has been participating, through the Clinical Trials
Transformation Initiative, in the development of recommendations
identifying principles for GCP training for investigators.\2\
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    \1\ Further information is available at: https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/EducationalMaterials/ucm112925.htm.
    \2\ https://www.ctti-clinicaltrials.org/what-we-do/study-start/gcp-training.
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V. Legal Authority

    We are issuing 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
ensure 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 clinical investigation.
---------------------------------------------------------------------------

    \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' 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.''
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    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 investigation 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 investigations, the data must be submitted in a PMA
application under section 515(c)(1)(A) of the FD&C Act.
    Under section 510(k) of the FD&C Act, device manufacturers are
required to submit a premarket notification to FDA before introducing
or delivering for introduction into interstate commerce for commercial
distribution a device, unless the device is exempt from premarket
notification. FDA reviews a premarket notification submission to
determine whether the device is substantially equivalent to a legally
marketed (predicate) device. Under section 513(i) of the FD&C Act,
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 investigation 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
investigation 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, as amended by the Cures Act
in 2016, FDA may grant an HDE if FDA finds that the device: (1) Is
designed to treat or diagnose a disease or condition that affects not
more than 8,000 individuals in the United States; (2) 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 (3) 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 investigations submitted in an HDE application support that
the probable benefits of the device outweigh its risks depends, in
part, on whether the investigation 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 513(f)(2) of the FD&C Act authorizes the submission of a
request for De Novo classification for a device for which there is no
legally marketed device upon which to base a substantial equivalence
determination, and authorizes FDA to classify the device subject to the
request under the criteria set forth in section 513(a)(1) of the FD&C
Act. Whether data from clinical investigations submitted in a request
for De Novo classification support the recommended classification
depends, in part, on whether the investigation 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 569B of the FD&C Act, which was added by the Food and Drug
Administration Safety and Innovation Act (Pub. L. 112-144) in 2012,
requires FDA to accept data from clinical investigations conducted
outside the United States, if the applicant demonstrates that such data
are adequate under FDA's applicable standards to support clearance or
approval of the device.
    Section 701(a) of the FD&C Act 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 investigations,
whether conducted inside or outside the United States, as reliable
evidence supporting an IDE, PMA, 510(k), PDP, request for De Novo
classification, or HDE application or submission.

VI. Analysis of 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.

VII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, 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 us 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). Executive Order 13771
requires that the costs associated with significant new regulations
``shall, to the extent permitted by law, be offset by the elimination
of existing costs associated with at least two prior regulations.'' We
believe that this final rule is not a significant regulatory action as
defined by Executive Order 12866. This final rule is not considered an
Executive Order 13771 regulatory action.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because small entities are not likely to incur more than one
percent of their revenue in costs to comply with the final rule, we
certify that the final rule will not have a significant economic impact
on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``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 $148
million, using the most current (2016) Implicit Price Deflator for the
Gross Domestic Product. This final rule would not result in an
expenditure in any year that meets or exceeds this amount.
    We have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the final rule. The full analysis of economic
impacts is available in the docket for this final rule (Ref. 1, Docket
No. FDA-2013-N-0080) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
    The final rule will require that data submitted by sponsors and
applicants from clinical investigations conducted outside the United
States to support an IDE application, a 510(k) submission, a request
for De Novo classification, a PMA application, a PDP application, or an
HDE application be from investigations conducted in accordance with
GCP. We define GCP as a standard for the design, conduct, performance,
monitoring, auditing, recording, analysis, and reporting of clinical
investigations in a way that provides assurance that the data and
results are credible and accurate and that the rights, safety, and
well-being of subjects are protected. GCP includes the review and
approval by an IEC before initiating an investigation, continuing IEC
review of ongoing investigations, and obtaining and documenting the
freely given informed consent of subjects. The changes require a
statement regarding compliance with our regulations for human subject
protection, IRBs, and IDEs when the investigations are conducted in the
United States. With the above described changes, the rule is intended
to update our standards of acceptance of data from clinical
investigations and to help ensure the quality and integrity of data
obtained from these investigations and the protection of human
subjects.
    We have not quantified the benefits of the final rule that would
come from the greater assurance of clinical data quality and integrity
and human subject protection, particularly as it pertains to clinical
investigations conducted outside the United States. One-time costs
would arise to learn the requirements of the rule, and annually
recurring costs would arise from increased labor associated with
obtaining, documenting, and maintaining records to meet the rule's
requirements for those that did not already meet the requirements.
Total estimated annualized costs of complying with these requirements,
over 10 years, range from $0.8 million to $22.1 million with a 7
percent discount rate and range from $0.7 million to $22.0 million with
a 3 percent discount rate.
    Table 1 summarizes our estimate of the annualized costs and the
annualized benefits of the final rule.

                                       Table 1--Summary of Benefits, Costs and Distributional Effects of the Rule
                                                                      [$ millions]
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                                                                                Units
                                                                                ---------------------------------------
                           Category                              Primary        Low          High                                  Period       Notes
                                                                 estimate     estimate     estimate       Year       Discount     covered
                                                                                dollars      rate (%)     (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized...............................................  ...........  ...........  ...........         2016            7           10  ...........
    Monetized $millions/year.................................  ...........  ...........  ...........         2016            3           10  ...........
    Annualized...............................................  ...........  ...........  ...........         2016            7           10  ...........

    Quantified...............................................  ...........  ...........  ...........         2016            3           10  ...........
                                                              ------------------------------------------------------------------------------------------
    Qualitative..............................................     Increased collection of information that provides greater assurance of clinical data
                                                                                quality and integrity and human subject protection.
                                                              ------------------------------------------------------------------------------------------
Costs:
    Annualized...............................................         $7.4         $0.8        $22.1         2016            7           10  ...........
    Monetized $millions/year.................................          7.3          0.7         22.0         2016            3           10  ...........
    Annualized...............................................  ...........  ...........  ...........         2016            7           10  ...........
    Quantified...............................................  ...........  ...........  ...........         2016            3           10  ...........
    Qualitative..............................................  ...........  ...........  ...........  ...........  ...........  ...........  ...........
Transfers:
    Federal..................................................  ...........  ...........  ...........         2016            7           10  ...........
    Annualized...............................................  ...........  ...........  ...........         2016            3           10  ...........
                                                              ------------------------------------------------------------------------------
    Monetized $millions/year.................................  From: