On February 21, 2019 the new US FDA rule on medical device clinical investigations conducted outside the United States (OUS) became effective. In this post, we would like to discuss the difference between the old and the new regulation and what is now required of sponsors by the FDA.

The new rule was triggered by the increasingly global nature of clinical research. Today, many clinical investigations of medical devices are conducted in locations OUS and the data produced is submitted to the FDA to support an IDE (Investigational Device Exemption), device marketing application or submission.  The FDA wishes to accept such data from well-designed and well-conducted clinical investigations performed OUS but wants to make sure that they were conducted in a manner similar to studies conducted in the US under FDA guidance. The agency wants the studies to be conducted in accordance with GCP, for the supporting information provided to be applicable, and for the FDA to be able to validate the data from the investigation through an onsite inspection if necessary. Under this new rule, the FDA’s intention is to achieve more uniformity since it wants to accept quality data from both clinical investigations conducted within and outside the United States equally, for whatever the application or submission type.

The new FDA rule applies to all regulatory pathways applicable to medical devices, including 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). By having the requirements for acceptance of data from clinical investigations conducted outside the United States the same for all device marketing applications and submissions, greater assurance of the quality and integrity of the data from investigations OUS can be achieved.

The previous version of the regulations stated that investigators located OUS were expected to conduct clinical studies of medical devices in accordance with the “Declaration of Helsinki” or the laws and regulations of the country in which the research was conducted, whichever accorded greater protection to the human subjects.

With the new rule, entitled “Human Subject Protection; Acceptance of Data From Clinical Investigations for Medical Devices,” the Agency amended its regulations on the acceptance of clinical data arising from clinical studies of medical devices conducted both inside and OUS with the purpose of ensuring quality and integrity of the data obtained from these investigations and the protection of human subjects.

For investigations conducted in the US, the rule requires applicants and sponsors to state whether the investigation complied with 21 CFR, parts 50, 56, and 812. These regulations address data quality, integrity and human subject protection and are considered part of the FDA’s GCP regulations.

For clinical investigations conducted OUS, the US FDA requires that these investigations are conducted in accordance with good clinical practice (GCP). Supporting information must be submitted to the agency which proves the conformance with GCP and the data should be available for possible FDA inspections.

Compliance with GCP

Compliance with GCP should be demonstrated by 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. This includes individuals whose specimens are used in investigations of medical devices. The new FDA rule imposes obligations on sponsors of medical device studies to make statements and provide information describing in detail how their investigations comply with GCP.

Further requirements vary however depending on whether the investigation is for a significant risk device or a nonsignificant risk device (classification must be done by the clinical study sponsor, but the FDA does not expect foreign IECs to necessarily make such differentiation).

For clinical investigations of significant risk medical devices, the FDA must be supplied with information on the incentives offered to participants. For clinical studies of nonsignificant risk devices, this information should be collected and provided to the FDA only on request. However, information on incentives should be included in the ICFs, reviewed and approved by IECs for both kinds of investigations.

Greater Flexibility

A certain degree of flexibility has been granted by the new FDA rule. In cases of non-complete GCP compliance, sponsors of clinical trials may submit a statement to the FDA justifying the reasons for non-compliance or requesting a waiver. This may be required, for example, when the investigation was conducted in a location where the applicable rules and regulations do not completely cover the provisions of GCP. The statement should explain the reason for not conducting the investigation in accordance with GCP and a description of the steps taken to ensure that the data and results are credible, accurate, and that the rights, safety, and well-being of subjects have been adequately protected.

Which GCP standard to follow?

The new rule states that clinical investigations OUS should be conducted in conformance with GCP. However, the FDA did not specify the GCP standard which should be followed. This is related to the fact that currently there is no one harmonized, international GCP standard for clinical studies of medical devices. ICH E6 – mostly applicable to clinical studies of pharmaceutical products – and ISO 14155:2011 are the two best known international GCP guidelines.

As a result, the FDA has allowed some flexibility when choosing the GCP standard. However, it has officially recognized the ISO standard for medical device investigations as the acceptable standard for clinical studies conducted OUS, and therefore OUS studies conducted in compliance with ISO are deemed to be in compliance with GCP. The FDA stated that sponsors and applicants who follow ISO 14155:2011 in the conduct of clinical investigations will be able to meet the requirement in § 812.28(a)(1) of the new rule as well as the local laws and regulations of the countries where the investigations are conducted.

The application of GCP standards in the conduct of clinical investigations OUS is in addition to the local laws and regulations, to the extent that the local laws and regulations do not incorporate such a standard.

Supporting information

The information which should be submitted to the FDA by sponsors of clinical investigations conducted OUS should include:

The names of all the investigators, and the names and addresses of all facilities that took part in the investigation, such as the investigational sites, laboratories, and specimen collection sites and where records relating to the investigation are maintained.

Information confirming investigator qualifications (typically in the form of CV or other similar document) confirming that the investigator is qualified to serve as an investigator based on his or her training and experience specifically related to the clinical investigation

Description of the research facilities including sufficient information for the FDA to make a judgement about the adequacy of the facilities to execute the investigation and meet its requirements (e.g., 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).

A detailed summary of the protocol and results of the investigation

Availability of data for inspections

One condition of the acceptance of data from investigations conducted OUS is that the FDA should be able to validate the data from such investigations through an onsite inspection, or through other appropriate means, if the agency deems it necessary.

Retention of records

Finally, the new rule specifies the period of retention of study records.

It requests that the sponsor must retain the required records of clinical investigations conducted OUS for at least 2 years after an Agency decision on that application or submission or, if the investigation is submitted in support of an IDE, for 2 years after termination or completion of the IDE.

In summary, the FDA recognizes the international nature of clinical research and wishes to accept data obtained in clinical investigations OUS in support of an IDE application, a 510(k) submission, a PMA application, a PDP application, or an HDE application. However, in its new rule, the FDA has updated the criteria for acceptance of data from clinical investigations to help ensure the quality and integrity of data obtained from those studies and the protection of human subjects. The new rule makes it clear that the clinical investigations should be conducted in conformance with a GCP standard such as ICH E6 or ISO 14155:2011 and will require the sponsors to make statements and submit the supporting information demonstrating conformity.