The US Food and Drug Administration (FDA) on Tuesday finalized a rule that requires medical device clinical investigations conducted outside the US to flexibly conform with good clinical practice (GCP) standards.

FDA said it 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."

The new rule requires that sponsors and applicants provide statements and information about how their clinical investigations conform with GCP.

"This applies to clinical data submitted to support investigational device exemptions (IDE), premarket notifications (510(k)), requests for De Novo classification, premarket approvals (PMA), product development protocols (PDP), and humanitarian device exemptions (HDE)," FDA said, noting that it believes the requirements "provide flexibility for medical device sponsors conducting multinational clinical trials by allowing them to describe the standard for good clinical practice they followed."

The final rule also amends the IDE, 510(k) and HDE regulations for FDA acceptance of data from clinical investigations conducted within the US to require a statement regarding compliance with FDA regulations for human subject protection, institutional review boards, and IDEs.

"This change is intended to provide consistency across different submission or application types," FDA said.

In addition to the rule, FDA also published guidance on Tuesday, known as "Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions." The question and answer guidance provides clarifications and recommendations to help ensure studies conducted in the US or foreign countries comply with the new rule and revised regulations.

Changes From Proposal to Final Rule

In terms of changes between the 2013 proposed rule and Tuesday’s final rule, FDA said they are "primarily for clarity and accuracy, to reduce burden, and to provide flexibility in meeting regulatory requirements."

Several of the main changes from the proposed rule include:

• "Clarifying that the rule applies to clinical data from ‘investigations’ as defined in § 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 § 812.28(a)(2), which identifies different supporting information requirements based on whether the investigation is for a significant risk device or a nonsignificant risk device, or meets the exemption criteria in § 812.2(c). Also, for investigations meeting the exemption criteria in § 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 § 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 § 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 § 812.2(c), the final rule requires that information on incentives be made available upon FDA’s request. We made this change because of concerns that incentives can affect data integrity for all investigations. We do not believe this requirement will be overly burdensome…
• Adding a waiver provision in new § 812.28(c) to allow sponsors and applicants to request a waiver of any applicable requirements under § 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."

International Harmonization

Several commenters on the proposed rule raised concerns that an internationally accepted GCP standard for devices does not exist and that this rule’s finalization should wait until such a standard is established.

But FDA said it "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 [International Council on Harmonisation] 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."

The agency also noted that the final rule "does not identify a specific GCP standard for sponsors and applicants to follow. Instead, the rule includes a definition of GCP in § 812.28(a)(1), which is consistent with the definition in § 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."