Human Subject Protection; Acceptance of Data From Clinical Investigations for Medical Devices, 7366-7388 [2018-03244]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 83, Number 35 (Wednesday, February 21, 2018)]
[Rules and Regulations]
[Pages 7366-7388]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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, 240-402-7911.

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

[[Page 7367]]

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

[[Page 7368]]

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

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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

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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

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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

[[Page 7372]]

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.

[[Page 7373]]

    (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,

[[Page 7374]]

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

[[Page 7375]]

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.

[[Page 7376]]

    (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

[[Page 7377]]

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

[[Page 7378]]

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.

[[Page 7379]]

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

[[Page 7380]]

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

[[Page 7381]]

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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

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.''
---------------------------------------------------------------------------

    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

[[Page 7382]]

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]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                      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  ...........

[[Page 7383]]

 
    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:
                                                               To:                                    ...........
                                                              ------------------------------------------------------------------------------
    Other....................................................  ...........  ...........  ...........         2016            7           10  ...........
                                                              ------------------------------------------------------------------------------
    Annualized...............................................  ...........  ...........  ...........         2016            3           10  ...........
                                                              ------------------------------------------------------------------------------
    Monetized $millions/year.................................  From:
                                                               To:                                    ...........
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.............................................................................................................
    Small Business: None................................................................................................................................
    Wages: None.........................................................................................................................................
    Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Table 2 presents a summary of the Executive Order 13771 impacts of 
the final rule over an infinite time horizon.

                                                            Table 2--E.O. 13771 Summary Table
                                               [In $ millions 2016 dollars, over an infinite time horizon]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Lower bound     Upper bound                     Lower bound     Upper bound
                                                           Primary (7%)        (7%)            (7%)        Primary (3%)        (3%)            (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs..................................           101.7             7.9           311.6           232.0            13.0           721.7
Present Value of Cost Savings...........................             0.0             0.0             0.0             0.0             0.0             0.0
Present Value of Net Costs..............................           101.7             7.9           311.6           232.0            13.0           721.7
Annualized Costs........................................             7.1             0.6            21.8             7.0             0.4            21.7
Annualized Cost Savings.................................             0.0             0.0             0.0             0.0             0.0             0.0
Annualized Net Costs....................................             7.1             0.6            21.8             7.0             0.4            21.7
--------------------------------------------------------------------------------------------------------------------------------------------------------

VIII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). The 
title, description, and respondent description of the information 
collection provisions are shown in the following paragraphs with an 
estimate of the annual reporting and recordkeeping burden. Included in 
the estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    Title: Human Subject Protection; Data Requirements for Medical 
Device Related Clinical Investigations (OMB control number 0910-0741)
    Description: In this document is a discussion of the regulatory 
provisions we believe are subject to the PRA and the probable 
information collection burden associated with these provisions.
    Description of Respondents: The reporting and recordkeeping 
requirements referenced in this document are imposed on a medical 
device sponsor or applicant.

Section 807.87--Information Required in a Premarket Notification 
Submission (OMB Control Number 0910-0120)

    Section 807.87 is being amended to address requirements for 510(k) 
submissions supported by clinical data. For clinical investigations 
conducted in the United States, submitters will be required to submit a 
statement as described in Sec.  807.87(j)(1). For clinical 
investigations conducted outside the United States, submitters will be

[[Page 7384]]

required to submit the information as described in Sec.  807.87(j)(2).

Section 812.27--Report of Prior Investigations (OMB Control Number 
0910-0078)

    Section 812.27 is being amended to address requirements for IDE 
applications supported by clinical data. For clinical investigations 
conducted in the United States, sponsors will be required to submit a 
statement as described in Sec.  812.27(b)(4)(i). For clinical 
investigations conducted outside the United States, sponsors will be 
required to submit the information as described in Sec.  
812.27(b)(4)(ii).

Section 812.28--Acceptance of Data From Clinical Investigations 
Conducted Outside the United States (OMB Control Number 0910-0078)

    Section 812.28 is being added to address the requirements for 
acceptance of foreign clinical data to support an IDE or a device 
marketing application or submission. The sponsor or applicant will be 
required to submit a statement as described in Sec.  812.28(a)(1); 
provide a description of the actions the sponsor or applicant took to 
ensure that the research conformed to GCP that includes the information 
in Sec.  812.28(b)(1) through (12) or a cross-reference to another 
section of the application or submission where the information is 
located; submit requests for waivers as described in Sec.  812.28(c); 
and retain the records as described in Sec.  812.28(d).

Section 812.140--Records Retention (OMB Control Number 0910-0078)

    Section 812.140 is being amended to address record retention 
requirements for investigators and sponsors. An investigator or sponsor 
will be required to maintain records as described in Sec.  812.140(d).

Section 814.20--Application (OMB Control Number 0910-0231)

    Section 814.20 is being amended to address requirements for a PMA 
application supported by data from clinical investigations conducted 
outside the United States. The applicant will be required to submit the 
information as described in Sec.  814.20(b)(6)(ii)(C).

Section 814.104--Original Applications (OMB Control Number 0910-0332)

    Section 814.104 is being amended to address submission of data from 
clinical investigations in an HDE application. To the extent the 
applicant includes data from clinical investigations, the applicant 
will be required to include the information and statements as described 
in Sec.  814.104(b)(4)(i).

                                                     Table 3--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                    Number of
            21 CFR section/activity                 Number of     responses per   Total annual         Average burden per response          Total hours
                                                   respondents     respondent       responses
--------------------------------------------------------------------------------------------------------------------------------------------------------
807.87(j)--Human subject protection statement             1,500               1           1,500  .25 (15 minutes).......................             375
 and information in a premarket notification
 submission supported by clinical data.
812.27(b)(4)(i)--Report of prior                            400               1             400  1......................................             400
 investigations; U.S.
812.27(b)(4)(ii)--Report of prior                           100               1             100  .25 (15 minutes).......................              25
 investigations; outside the U.S.
812.28(a)(1)--Data from clinical investigations           1,500               1           1,500  .25 (15 minutes).......................             375
 \2\.
812.28(b)--Description regarding GCP \2\.......           1,500               1           1,500  10.....................................          15,000
812.28(c)--Waivers \2\.........................              10               1              10  1......................................              10
814.20--Application information................              10               1              10  .50 (30 minutes).......................               5
814.104--Original applications statements and                10               1              10  8......................................              80
 information.
                                                --------------------------------------------------------------------------------------------------------
    Total......................................  ..............  ..............  ..............  .......................................          16,270
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ No precise data is available for requests for De Novo classifications.


                               Table 4--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
     21 CFR section/activity         Number of      records per    Total annual         per         Total hours
                                   recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
812.28(d)--Records from clinical           1,500               1           1,500               1           1,500
 investigations conducted
 outside the United States \2\..
812.140--Retention period.......              10               1              10               1              10
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............           1,510
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ No precise data is available for requests for De Novo classifications.

    The total estimated burden imposed by these information collection 
requirements is 17,780 annual hours. The estimated burden is based on 
the most recent empirical data in the relevant collections with the 
numbers updated to reflect the current burden of these requirements.
    It should be noted that while the information collection 
requirements referenced in this document are revisions to current 
approved information collections, these collection requirements are 
being submitted to OMB as a new information collection (OMB control 
number 0910-0741), with the expectation the currently approved 
requirements will be amended. As such the following collections of 
information will be amended and submitted to OMB for approval as 
revisions to currently approved information collections once the rule 
is finalized and the collections are due for renewal. The collections 
to

[[Page 7385]]

be amended include: Investigational Device Exemptions Reports and 
Records--21 CFR part 812, OMB control number 0910-0078; Premarket 
Notification--21 CFR part 807, subpart E, OMB control number 0910-0120; 
Premarket Approval of Medical Devices--21 CFR part 814, subparts A 
through E, OMB control number 0910-0231; and Medical Devices: 
Humanitarian Use Devices--21 CFR part 814, subpart H, OMB control 
number 0910-0332.
    The information collection provisions in this final rule have been 
submitted to OMB for review as required by section 3507(d) of the PRA.
    Before the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

IX. Federalism

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

X. Reference

    The following reference is on display in the Dockets Management 
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 
1061, Rockville, MD 20852, and is available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; it is also 
available electronically at https://www.regulations.gov.

1. Regulatory Impact Analysis of the Final Rule to Human Subject 
Protection; Acceptance of Data from Clinical Investigations for 
Medical Devices, Docket No. FDA-2013-N-0080.

List of Subjects

21 CFR Part 807

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

21 CFR Part 812

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

21 CFR Part 814

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

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

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

0
1. The authority citation for part 807 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 360, 360c, 360e, 360i, 
360j, 360bbb-8b, 371, 374, 381, 393; 42 U.S.C. 264, 271.


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


Sec.  807.87   Information required in a premarket notification 
submission.

* * * * *
    (j) For a submission supported by clinical data:
    (1) If the data are from clinical investigations conducted in the 
United States, a statement that each investigation was conducted in 
compliance with applicable requirements in the protection of human 
subjects regulations in part 50 of this chapter, the institutional 
review boards regulations in part 56 of this chapter, or was not 
subject to the regulations under Sec.  56.104 or Sec.  56.105, and the 
investigational device exemptions regulations in part 812 of this 
chapter, or if the investigation was not conducted in compliance with 
those regulations, a brief statement of the reason for the 
noncompliance.
    (2) If the data are from clinical investigations conducted outside 
the United States, the requirements under Sec.  812.28 of this chapter 
apply. If any such investigation was not conducted in accordance with 
good clinical practice (GCP) as described in Sec.  812.28(a) of this 
chapter, include either a waiver request in accordance with Sec.  
812.28(c) of the chapter or a brief statement of the reason for not 
conducting the investigation in accordance with GCP and a description 
of steps taken to ensure that the data and results are credible and 
accurate and that the rights, safety, and well-being of subjects have 
been adequately protected.
* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

0
3. The authority citation for part 812 is revised to read as follows:

    Authority:  21 U.S.C. 331, 351, 352, 353, 355, 360, 360c-360f, 
360h-360j, 360bbb-8b, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C. 
216, 241, 262, 263b-263n.


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


Sec.  812.3   Definitions.

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

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


Sec.  812.27   Report of prior investigations.

* * * * *
    (b) * * *
    (4)(i) If data from clinical investigations conducted in the United 
States are provided, a statement that each investigation was conducted 
in compliance with applicable requirements in the protection of human 
subjects regulations in part 50 of this chapter, the institutional 
review boards regulations in part 56 of this chapter, or was not 
subject to the regulations under Sec.  56.104 or Sec.  56.105, and the 
investigational device exemptions regulations in this part, or if any 
such investigation was not conducted in compliance with those 
regulations, a brief statement of the reason for the noncompliance. 
Failure or inability to comply with these requirements does not justify 
failure to provide information on a relevant clinical investigation.
    (ii) If data from clinical investigations conducted outside the 
United States are provided to support the IDE, the requirements under 
Sec.  812.28 apply. If any such investigation was not conducted in 
accordance with good clinical practice (GCP) as described in Sec.  
812.28(a), the report of prior investigations shall include either a 
waiver request in accordance with Sec.  812.28(c) or a brief statement 
of the

[[Page 7386]]

reason for not conducting the investigation in accordance with GCP and 
a description of steps taken to ensure that the data and results are 
credible and accurate and that the rights, safety, and well-being of 
subjects have been adequately protected. Failure or inability to comply 
with these requirements does not justify failure to provide information 
on a relevant clinical investigation.

0
6. Section 812.28 is added to subpart B to read as follows:


Sec.  812.28   Acceptance of data from clinical investigations 
conducted outside the United States.

    (a) Acceptance of data from clinical investigations conducted 
outside the United States to support an IDE or a device marketing 
application or submission (an application under section 515 or 520(m) 
of the Federal Food, Drug, and Cosmetic Act, a premarket notification 
submission under section 510(k) of the Federal Food, Drug, and Cosmetic 
Act, or a request for De Novo classification under section 513(f)(2) of 
the Federal Food, Drug, and Cosmetic Act). FDA will accept information 
on a clinical investigation conducted outside the United States to 
support an IDE or a device marketing application or submission if the 
investigation is well-designed and well-conducted and the following 
conditions are met:
    (1) A statement is provided that the investigation was conducted in 
accordance with good clinical practice (GCP). For the purposes of this 
section, GCP is defined as a standard for the design, conduct, 
performance, monitoring, auditing, recording, analysis, and reporting 
of clinical 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 (or provision of a favorable opinion) by an independent ethics 
committee (IEC) before initiating an investigation, continuing review 
of an ongoing investigation by an IEC, and obtaining and documenting 
the freely given informed consent of the subject (or a subject's 
legally authorized representative, if the subject is unable to provide 
informed consent) before initiating an investigation. GCP does not 
require informed consent in life-threatening situations when the IEC 
reviewing the investigation finds, before initiation of the 
investigation, that informed consent is not feasible and either that 
the conditions present are consistent with those described in Sec.  
50.23 or Sec.  50.24(a) of this chapter, or that the measures described 
in the protocol or elsewhere will protect the rights, safety, and well-
being of subjects.
    (2) In addition to the information required elsewhere in parts 807, 
812, and 814 of this chapter, as applicable, the information in 
paragraph (b) of this section is submitted, as follows:
    (i) For an investigation of a significant risk device, as defined 
in Sec.  812.3(m), the supporting information as described in paragraph 
(b) of this section is submitted.
    (ii) For an investigation of a device, other than a significant 
risk device, the supporting information as described in paragraphs 
(b)(1), (4), (5), (7) through (9), and (11) of this section is 
submitted, and the supporting information as described in paragraph 
(b)(10) of this section and the rationale for determining the 
investigation is of a device other than a significant risk device are 
made available for agency review upon request by FDA.
    (iii) For a device investigation that meets the exemption criteria 
in Sec.  812.2(c), the supporting information as described in 
paragraphs (b)(1), (4), (5), (7) through (11) of this section and the 
rationale for determining the investigation meets the exemption 
criteria in Sec.  812.2(c) are made available for agency review upon 
request by FDA.
    (3) FDA is able to validate the data from the investigation through 
an onsite inspection, or through other appropriate means, if the agency 
deems it necessary.
    (b) Supporting information. A sponsor or applicant who submits data 
from a clinical investigation conducted outside the United States to 
support an IDE or a device marketing application or submission, in 
addition to information required elsewhere in parts 807, 812, and 814 
of this chapter, as applicable, shall provide a description of the 
actions the sponsor or applicant took to ensure that the research 
conformed to GCP as described in paragraph (a)(1) of this section. The 
description is not required to duplicate information already submitted 
in the application or submission. Instead, the description must provide 
either the following information, as specified in paragraph (a)(2) of 
this section, or a cross-reference to another section of the 
application or submission where the information is located:
    (1) The names of the investigators and the names and addresses of 
the research facilities and sites where records relating to the 
investigation are maintained;
    (2) The investigator's qualifications;
    (3) A description of the research facility(ies);
    (4) A detailed summary of the protocol and results of the 
investigation and, should FDA request, case records maintained by the 
investigator or additional background data such as hospital or other 
institutional records;
    (5) Either a statement that the device used in the investigation 
conducted outside the United States is identical to the device that is 
the subject of the submission or application, or a detailed description 
of the device and each important component (including all materials and 
specifications), ingredient, property, and principle of operation of 
the device used in the investigation conducted outside the United 
States and a comparison to the device that is the subject of the 
submission or application that indicates how the device used in the 
investigation is similar to and/or different from the device that is 
the subject of the submission or application;
    (6) If the investigation is intended to support the safety and 
effectiveness of a device, a discussion demonstrating that the data and 
information constitute valid scientific evidence within the meaning of 
Sec.  860.7 of this chapter;
    (7) The name and address of the IEC that reviewed the investigation 
and a statement that the IEC meets the definition in Sec.  812.3(t). 
The sponsor or applicant must maintain records supporting such 
statement, including records describing the qualifications of IEC 
members, and make these records available for agency review upon 
request;
    (8) A summary of the IEC's decision to approve or modify and 
approve the investigation, or to provide a favorable opinion;
    (9) A description of how informed consent was obtained;
    (10) A description of what incentives, if any, were provided to 
subjects to participate in the investigation;
    (11) A description of how the sponsor(s) monitored the 
investigation and ensured that the investigation was carried out 
consistently with the protocol; and
    (12) A description of how investigators were trained to comply with 
GCP (as described in paragraph (a)(1) of this section) and to conduct 
the investigation in accordance with the protocol, and a statement on 
whether written commitments by investigators to comply with GCP and the 
protocol were obtained. Any signed written commitments by investigators 
must be maintained by the sponsor or applicant and made available for 
agency review upon request.
    (c) Waivers. (1) A sponsor or applicant may ask FDA to waive any 
applicable

[[Page 7387]]

requirements under paragraphs (a)(1) and (b) of this section. A waiver 
request may be submitted in an IDE or in an amendment or supplement to 
an IDE, in a device marketing application or submission (an application 
under section 515 or 520(m) of the Federal Food, Drug, and Cosmetic 
Act, a premarket notification submission under section 510(k) of the 
Federal Food, Drug, and Cosmetic Act, or a request for De Novo 
classification under section 513(f)(2) of the Federal Food, Drug, and 
Cosmetic Act) or in an amendment or supplement to a device marketing 
application or submission, or in a pre-submission. A waiver request is 
required to contain at least one of the following:
    (i) An explanation why the sponsor's or applicant's compliance with 
the requirement is unnecessary or cannot be achieved;
    (ii) A description of an alternative submission or course of action 
that satisfies the purpose of the requirement; or
    (iii) Other information justifying a waiver.
    (2) FDA may grant a waiver if it finds that doing so would be in 
the interest of the public health.
    (d) Records. A sponsor or applicant must retain the records 
required by this section for a clinical investigation conducted outside 
the United States as follows:
    (1) If the investigation is submitted in support of an IDE, for 2 
years after the termination or completion of the IDE; and
    (2) If the investigation is submitted in support of a premarket 
approval application, a notice of completion of a product development 
protocol, a humanitarian device exemption application, a premarket 
notification submission, or a request for De Novo classification, for 2 
years after an agency decision on that submission or application.
    (e) Clinical investigations conducted outside of the United States 
that do not meet conditions. For clinical investigations conducted 
outside the United States that do not meet the conditions under 
paragraph (a) of this section, 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 investigation are credible and accurate and that the 
rights, safety, and well-being of subjects have been adequately 
protected.

0
7. Section 812.140 is amended by revising paragraph (d) to read as 
follows:


Sec.  812.140   Records.

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

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

0
8. The authority citation for part 814 is revised to read as follows:

    Authority:  21 U.S.C. 351, 352, 353, 360, 360c-360j, 360bbb-8b, 
371, 372, 373, 374, 375, 379, 379e, 381.


0
9. Section 814.15 is amended by revising paragraph (a); by removing 
paragraphs (b) and (c); by redesignating paragraphs (d) and (e) as 
paragraphs (b) and (c), respectively; and by removing the parenthetical 
sentence at the end of the section to read as follows:


Sec.  814.15   Research conducted outside the United States.

    (a) Data to support PMA. If data from clinical investigations 
conducted outside the United States are submitted to support a PMA, the 
applicant shall comply with the provisions in Sec.  812.28 of this 
chapter, as applicable.
* * * * *

0
10. Section 814.20 is amended by revising paragraphs (b)(6)(ii)(A) and 
(B) and adding paragraph (b)(6)(ii)(C) to read as follows:


Sec.  814.20   Application.

* * * * *
    (b) * * *
    (6) * * *
    (ii) * * *
    (A) For clinical investigations conducted in the United States, a 
statement with respect to each investigation that it either was 
conducted in compliance with the institutional review board regulations 
in part 56 of this chapter, or was not subject to the regulations under 
Sec.  56.104 or Sec.  56.105, and that it was conducted in compliance 
with the informed consent regulations in part 50 of this chapter; or if 
the investigation was not conducted in compliance with those 
regulations, a brief statement of the reason for the noncompliance. 
Failure or inability to comply with these requirements does not justify 
failure to provide information on a relevant clinical investigation.
    (B) For clinical investigations conducted in the United States, a 
statement that each investigation was conducted in compliance with part 
812 of this chapter concerning sponsors of clinical investigations and 
clinical investigators, or if the investigation was not conducted in 
compliance with those regulations, a brief statement of the reason for 
the noncompliance. Failure or inability to comply with these 
requirements does not justify failure to provide information on a 
relevant clinical investigation.
    (C) For clinical investigations conducted outside the United States 
that are intended to support the PMA, the requirements under Sec.  
812.28 of this chapter apply. If any such investigation was not 
conducted in accordance with good clinical practice (GCP) as described 
in Sec.  812.28(a), include either a waiver request in accordance with 
Sec.  812.28(c) or a brief statement of the reason for not conducting 
the investigation in accordance with GCP and a description of steps 
taken to ensure that the data and results are credible and accurate and 
that the rights, safety, and well-being of subjects have been 
adequately protected. Failure or inability to comply with these 
requirements does not justify failure to provide information on a 
relevant clinical investigation.
* * * * *

0
11. Section 814.45 is amended by revising paragraph (a)(5) to read as 
follows:


Sec.  814.45   Denial of approval of a PMA.

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

[[Page 7388]]


0
12. Section 814.46 is amended by revising paragraph (a)(4) to read as 
follows:


Sec.  814.46   Withdrawal of approval of a PMA.

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

0
13. Section 814.104 is amended by revising paragraph (b)(4)(i) to read 
as follows:


Sec.  814.104   Original applications.

* * * * *
    (b) * * *
    (4) * * *
    (i) In lieu of the summaries, conclusions, and results from 
clinical investigations required under Sec.  814.20(b)(3)(v)(B), 
(b)(3)(vi), and the introductory text of (b)(6)(ii), the applicant 
shall include the summaries, conclusions, and results of all clinical 
experience or investigations (whether adverse or supportive) reasonably 
obtainable by the applicant that are relevant to an assessment of the 
risks and probable benefits of the device and to the extent the 
applicant includes data from clinical investigations, the applicant 
shall include the statements described in Sec.  814.20(b)(6)(ii)(A) and 
(B) with respect to clinical investigations conducted in the United 
States and the information described in Sec.  814.20(b)(6)(ii)(C) with 
respect to clinical investigations conducted outside the United States; 
and
* * * * *

    Dated: February 13, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-03244 Filed 2-20-18; 8:45 am]
 BILLING CODE 4164-01-P