On Wednesday, February 21st, the FDA released a final rule entitled “Human Subject Protection; Acceptance of Data From Clinical Investigations for Medical Devices.” The new rule amends the Agency’s acceptance criteria regarding data generated from clinical trials conducted outside the US, stating that they must be conducted in compliance with the Agency’s GCP standards. The rule applies to sponsors or applicants of the following medical device submissions:
- Investigational device exemption (IDE) applications
- Premarket notification (510(k)) submissions
- Request for De Novo classifications
- Premarket approval (PMA) applications
- Product development protocol (PDP) applications
- Humanitarian device exemption (HDE) applications
The final rule states that these trials must be “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.”
Under the new rule, sponsors and applicants will now be required to provide statements concerning the trial’s GCP compliance when clinical data is submitted in support of device applications and submissions.
In a guidance document published alongside the final rule, FDA stated that “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, ethically derived data. Conformance with GCP is one way to help ensure clinical data are credible, accurate, and ethically procured.”
As such, sponsors relying on data from investigations conducted in the US will be required to state whether the investigation complied with 21 CFR parts 50, 56, and 812. “These regulations address data quality and integrity and human subject protection and are considered part of FDA’s GCP regulations.” Moreover, sponsors relying on data from trials conducted outside the US will be required to include a statement explaining how the investigations conform with GCP and provide supporting information that demonstrates this conformance.
Proposed vs. Final Rule
The rule was originally issued as a proposed rule on February 25, 2013. However, there are numerous changes between the recently published final rule and the proposed rule issued five years ago. Some of these changes include:
- Removal of proposed section 812.2(e), which “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.” This section was removed after FDA received comments indicating confusion concerning the scope of the rule.
- “Clarifies 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.”
- “Clarifies 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.”
- 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 section 812.2(c).” Furthermore, the specified supporting information for trials that meet the exemption criteria in section 812.2(c) must be maintained and available for review upon request by the FDA.
- Requires 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.”
- Changes “the requirements related to supporting information on incentives provided to subjects to require that the information be maintained for all clinical investigations but 8 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.”
- “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.”
- Explains that FDA may accept data from trials conducted outside the US that do not meet the conditions listed in section 812.28(a), if the Agency believes that “the data and results from such clinical investigations are credible and accurate and that the rights, safety, and wellbeing of subjects have been adequately protected.” Furthermore, the new rule clarifies that that sponsors can explain why a clinical investigation was not conducted in accordance with GCP.
- Changes “the requirement in proposed section 812.28(a)(2), now section 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.”
- Clarifies that the requirements of the final rule apply to requests for De Novo classifications.
Implications for International Harmonization?
After the proposed rule was published, the FDA received numerous comments regarding how the rule will impact international harmonization and the regulation of international trials. In response to these remarks, FDA stated that “it has and will continue to promote global harmonization in many aspects of medical device development and regulation.”
In both the final rule and the accompanying guidance document, FDA states that it does not intend to regulate clinical trials conducted outside the US. Furthermore, the Agency notes that it expects that “foreign clinical investigations will be conducted in accordance with local laws and regulations. The requirements outlined in the rule allow the flexibility needed to accommodate those 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. 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.”
In addition, “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 § 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.”
Implementation of New Requirements
The final rule is set to take effect on February 21, 2019. The Agency decided to wait a full year after releasing the new regulation in order to give sponsors and applicants ample time to make any necessary changes (i.e., to their internal operating procedures, study planning, etc.), and 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.
The FDA also notes that the rule will only apply to clinical trials that enroll the first subject on or after the effective date of the rule.