The US Food and Drug Administration (FDA) recently finalized a rule requiring medical device clinical investigations conducted outside the United States to conform to standards for good clinical practice (GCP).
The agency defined these practices 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."
FDA notes 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."
Access the full final rule here.
Requirements Under the New Final Rule
The new rule states that sponsors and applicants must 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. Regulators say this the change is "intended to provide consistency across different submission or application types.
Key Changes from Proposed Rule
The final rule presents a number of key changes from the proposed rule published in 2013. Regulators describe the changes as being made "primarily for clarity and accuracy, to reduce burden, and to provide flexibility in meeting regulatory requirements."
Here are a few of the most important changes in the final rule taken verbatim:
- "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."
- "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 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."
- "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."
- "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."
- "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."
Supporting Guidance Published
Along with the finalized rule, the agency also published a new guidance titled "Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions."
This question-and-answer guidance clarifies concepts and offers and recommendations to help ensure studies conducted both inside and outside the United States comply with the new rule and revised regulations.
Addressing International Harmonization Concerns
Some have expressed concern 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.
FDA defended their final rule, saying 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."
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