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Acceptance of Data from

Clinical Investigations for Medical Devices

John Doucet and Jayna Stohlman

Clinical Trials Program

Office of Device Evaluation 

Center for Devices and Radiological Health

March 19, 2019
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Publication Date: February 21, 2018

Final Rule

Human Subject Protection; Acceptance of Data From Clinical 

Investigations for Medical Devices

Associated Guidance

FDA Acceptance of Clinical Data to Support Medical

Device Applications and Submissions

Frequently Asked Questions 

Effective Date: February 21, 2019
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Purpose of Device Rule

• Update and clarify the requirements for FDA acceptance of clinical data 

– for all device application and submission types, and

– for investigations conducted inside and outside the United States

• Expressly incorporate good clinical practice (GCP)

– Ensure the quality and integrity of the data 

– Ensure the protection of human subjects

• Harmonize with drug regulations

• Ensure FDA’s decisions are based on valid, ethically derived data.
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Center for Devices and Radiological Health

Vision Statement

Patients in the U.S. have 

access to high-quality, safe, 

and effective medical devices 

of public health importance 

first in the world.
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• Background 

• Requirements for Acceptance of Data From Device Clinical Investigations

• FDA Implementation and Recommendations

• Questions

Agenda
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Objectives

Understand the following elements:

• The purpose of the requirements for acceptance of data from device clinical 

investigations 

• Documentation requirements from device clinical investigations to support 

premarket submissions

• Recommendations and resources for complying with the rule
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• Investigation - research involving one or more subjects to determine the safety 

or effectiveness of a device [812.3(h)]

– United States (US) investigation: conducted solely in US

– Outside US (OUS) investigation: conducted solely outside the US

– Multinational investigation: conducted at sites both within and outside the US

• Investigational Device Exemption (IDE) application: mechanism to request 

approval for a significant risk clinical investigation of an unapproved device or 

unapproved use of a device

• Marketing application or submission: Premarket Notification (510(k)), 

Request for De Novo Classification (De Novo), Premarket Approval Application 

(PMA), Product Development Protocol (PDP), Humanitarian Device Exemption 

(HDE) 

Definitions
Background
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Final Rule Timeline

Proposed Rule

issued 

February 25, 2013

Final Rule

Final Guidance

issued

February 21, 2018

Final Rule 

Webinar

Public comments 

received, incorporated 

into final rule

Requirements effective

February 21, 2019

GO

Evolution of

Human Subject Protection Standards

E.g., 1989, 1996, 2000, 2002, 2004, 2008 

amendments to the

“Declaration of Helsinki on Ethical 

Principles for Medical Research Involving 

Human Subjects”.
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Public Comments on the Proposed Rule

Key Feedback (13 entities)

• Application of the rule

– Investigations within scope (e.g., Nonsignificant risk investigations, In Vitro 

Diagnostic (IVD) investigations using de-identified biospecimens)

• Implementation of the rule

– Effective date

• International standards and other laws

– Lack of a harmonized international good clinical practice (GCP) standard

– Privacy laws that may vary by country

• Acceptance of data from noncompliant studies
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• Changes to the Final Rule

– Adjusted supporting information requirements to vary by study risk

– Delayed effective date (from 6 months to 1 year) 

– Added additional regulatory flexibility, such as a waiver provision 

• Other Information in the Preamble 

– Clarified that FDA’s policy, outlined in the FDA Guidance, “Informed Consent 

for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that 

are Not Individually Identifiable,” may be used to address informed consent 

for certain IVD studies using leftover, de-identified human specimens.

FDA’s Response to Public Comments
Requirements for Acceptance of Data from

Device Clinical Investigations
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• 21 CFR parts 807, 812, and 814 have been amended to identify 

criteria for acceptance of clinical data for all premarket submissions

– Investigational Device Exemption (IDE), Premarket Notification (510(k)), 

Request for De Novo Classification (De Novo), Premarket Approval 

Application (PMA), Product Development Protocol (PDP), Humanitarian 

Device Exemption (HDE) 

• The rule applies to clinical investigations that begin (enroll their first 

subject) on or after February 21, 2019

Scope of Final Rule 
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Supporting clinical data – Final Rule requirements apply

“...provided to support an IDE or device marketing application or submission; 

for example, when clinical data are submitted in:

• A 510(k) submission to demonstrate substantial equivalence,

• A PMA application to demonstrate a reasonable assurance of safety and 

effectiveness, or

• An HDE application to demonstrate reasonable assurance of safety and 

probable benefit.”

Supplementary clinical data – Final Rule requirements do not apply

Supporting Data vs. Supplementary Data

Reference: 83 FR 7366, see comment 5
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Good Clinical Practice (GCP)

An Established Framework

Reference: GCP defined in 21 CFR 812.28(a)(1)

IEC defined in 21 CFR 812.3(t)

GCP – “... 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.” 

Key Principles:

– Independent Ethics Committee (IEC)

• Initial review and approval, continuing review 

– Obtaining and documenting freely given informed consent prior to subject 

participation
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• Investigations conducted inside the U.S. comply with FDA GCP 

regulations including:

• 21 CFR 812 Investigational Device Exemptions

• 21 CFR 50 Protection for Human Subjects, 

Informed Consent (IC) Regulation

• 21 CFR 56 Institutional Review Boards (IRBs)

FDA GCP Regulations

Address data quality and integrity and 

protection of human subjects
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Final Rule Requirements

US Investigations

For acceptance of data that are from clinical investigations conducted 

inside the United States, the Final Rule requires that sponsors or 

applicants provide:

• A statement that each investigation was conducted in compliance 

with the applicable requirements in parts 21 CFR 50, 56, and 812

• If not conducted in compliance with these regulations, a brief

statement of the reason for noncompliance

Reference: Sections 807.87(j)(1), 812.27(b)(4)(i) and 814.20(b)(6)(ii)(A) & (B)
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1. A statement that each investigation was conducted in 

accordance with GCP.

• If not conducted in accordance with GCP include either:

 A waiver request in accordance with 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.

2. Supporting information to demonstrate conformance with GCP

Reference: Sections 807.87(j)(2), 812.27(b)(4)(ii), 814.20(b)(6)(ii)(C) and 812.28(a) 

Final Rule Requirements

OUS Investigations
20 Reference: §812.28(b)

OUS Investigations

Closer look at required Supporting Information

• Names and addresses of investigators and research 

facilities

• Investigator qualifications

• Summary of protocol and study results

• Description of the device

• Discussion demonstrating that the data and information 

constitute valid scientific evidence

• Adequately constituted IEC
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Reference: §812.28(b)

OUS Investigations

Closer look at required Supporting Information

• Summary of IEC’s decision to approve or modify and 

approve the clinical investigation

• Description of how informed consent was obtained

• Description of incentives provided to subjects 

• Description of how the study was monitored

• Investigator training and commitments

Requirements are not intended to be duplicative with information already included in the submission 

and may be cross-referenced
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• Based on sponsor’s or applicant’s risk determination

– Sponsor/applicant maintains documentation of the rationale for their 

determination 

• Submission requirements vary by risk

– Significant Risk investigations: Submission of all required elements

– Non-significant Risk investigations: Submission of some elements while 

others are to be available for agency review upon request

– Exempt investigations: Some elements are to be available for agency 

review upon request

OUS Investigations

Supporting Information to Submit to FDA

Reference: Significant Risk Device defined in 812.3(m)

Exempt study criteria given in 812.2(c)
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Regulatory Flexibility

1. Sponsors and applicants may choose a GCP standard that 

meets the regulatory definition

2. Allowance for explaining why GCP was not followed and other 

measures used to ensure data integrity and subject protections

3. Waiver(s) may be requested in accordance with §812.28(c)

Reference: 21 CFR 814.20(b)(6)(ii)(C), 807.87(j)(2) & 812.27(b)(4)(ii) 
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Summary of Provisions

For investigations that enroll the first subject on or after February 21, 2019

US OUS Multinational

IDE

510(k)

De Novo

PMA

HDE

PDP

Statement of 

compliance* 

with:

21 CFR 50

21 CFR 56

21 CFR 812

1. Statement of conformance 

with GCP**

2. Supporting information to 

demonstrate conformance** 

• US sites - Statement of compliance 

with FDA regulations*

• OUS sites - Statement of 

conformance with GCP and 

supporting information**

* Or a rationale for noncompliance

** Or a rationale for noncompliance or a waiver request
Implementation and Recommendations
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The following guidances and associated acceptance checklists have 

been updated to incorporate provisions of the Final Rule:

– Refuse to Accept Policy for 510(k)s

– Acceptance and Filing Reviews for Premarket Approval 

Applications (PMAs) 

Acceptance Review
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Acceptance Review 

An Example 

Scope

U.S. Investigations

OUS Investigations

[https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm315014.pdf]
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Acceptance Review

Scope

[https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm315014.pdf]

• Defines applicability

• Includes reference to effective date

• Describes which of the subsequent 

questions apply (U.S., OUS, or 

multinational investigations)

• Provides link to the FAQ Guidance
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Acceptance Review

U.S. Investigations

[https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm315014.pdf]
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Acceptance Review

OUS Investigations

[https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm315014.pdf]
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There may be situations where investigations conducted OUS are 

not able to fully conform to GCP and/or are not able to demonstrate 

conformity to GCP, as described by 21 CFR 812.28(a).

Waiver Requests

A sponsor or applicant may ask the FDA to 

waive any applicable requirements by 

submitting a waiver request prior to or within 

an IDE or marketing submission or application

Reference: Section 812.28(c)
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A Waiver Request is required to include 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

Waiver Requests

What to Submit

Reference: 21 CFR 812.28(c)(1)
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As part of a premarket submission:

– In an IDE, or an Amendment or Supplement to an IDE;

– In a device marketing application or submission, or in an 

Amendment or Supplement to a device marketing application 

or submission;

As a standalone Waiver Request:

– Submit to Document Control Center

– Clearly identify that the submission is a Waiver Request in 

accordance with 21 CFR 812.28(c)

Waiver Requests

When and How to Submit
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Waiver Requests

How we communicate decisions

Determination on acceptability of waiver will be determined on a case-by-case basis.

Within a marketing application or submission, 

or an IDE (report of prior investigations)

• No formal communication with respect to whether a 

waiver request was granted or denied, unless the decision 

impacts FDA’s acceptance of the data and results in 

deficiencies to be addressed, in which case information 

will be provided in deficiency letters.

• Final decision on a submission or application does not 

imply whether or not a waiver request was granted or 

denied.

Other Waiver Requests:

• In a “pre-submission”; or

• In a IDE submission (when pertaining to 

the subject IDE)

• Decision to grant or deny the waiver request is 

communicated in a letter.
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Clearly identify in the premarket submission or application:

• Whether it contains data from OUS clinical investigations that are subject to 21 CFR 

812.28 (cover letter)

• Location of all required elements under 21 CFR 812.28:

– Within the subject submission or application

– Cross-reference to previously submitted materials

– Page references to respective clinical investigation reports, etc.

• Whether the submission includes statements of the reasons for not conducting the 

investigation in accordance with GCP, or a waiver is being requested or was previously 

granted

Recommendations for Submissions
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• Study Risk Determination for OUS 

investigations

• Pre-Submission: General Questions 

about compliance

Q-Submission Program
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• The final rule provides clarity and consistency for acceptance of clinical data for 

all premarket application and submission types for both U.S. and OUS 

investigations.

– Applies to investigations beginning on or after February 21, 2019

• The rule requires that data submitted from clinical investigations be from 

investigations conducted in accordance with GCP.

• It is the FDA’s intent to ensure that quality data are used to support IDEs and 

marketing applications and submissions, and that the rights, safety, and wellbeing of human subjects have been adequately protected.

Conclusions
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• Guidance

– Acceptance of Clinical Data to Support Medical Device Applications and 

Submissions Frequently Asked Questions

– Guidance on Informed Consent for In Vitro Diagnostic Device Studies 

Using Leftover Human Specimens that are Not Individually Identifiable

• GCP Standards

– ISO 14155: Clinical investigation of medical devices for human subjects 

– Good clinical practice 

– ICH E6: Good Clinical Practice: Consolidated Guidance

• FDA Help

– CDRHClinicalEvidence@fda.hhs.gov

Resources
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Questions?

Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

Slide Presentation, Transcript and Webinar Recording will be 

available at:

http://www.fda.gov/training/cdrhlearn

Under the heading: How to Study and Market Your Device; 

Subheading: Clinical Studies/Investigational Device 

Exemption (IDE)

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