New draft guidance has just been issued by the US Food and Drug Administration (FDA), which aims to make it easier for medical device companies to rely on data obtained from clinical studies conducted outside the United States (conveniently termed ‘OUS’ studies by the FDA ).  Naturally, this is provided that those studies are conducted to appropriate federal standards.

The draft guidance document (1) is closely related to a rule proposed by FDA back in February 2013 (2), which proposed a requirement that all clinical studies conducted outside the US in support of a device application comply with US regulations on good clinical practice (GCP).

The goal, regulators explained, was to promote consistency in the trials whilst assuring that human subjects participating in the trials were given adequate protection. The FDA now accepts data from foreign-conducted clinical studies meeting requirements of code of Federal Regulations 21 CFR 812-14.  This states that the data must be scientifically valid and must have been collected in accordance with the ethical guidelines of the Declaration of Helsinki or local laws (whichever offers stronger protection to research subjects).

These data are most commonly used in support of an application that includes data from the US, but the FDA encourages sponsors to discuss plans with them if the application will be “based solely on foreign clinical data”. Those requirements are less stringent than required for clinical trials conducted within the US, which are held to various US-specific regulations (e.g. 21 CFR 56 for IRBs and 21 CFR 50 for informed consent).

In this newest draft FDA guidance, the change regulators need to account for is that medical device trials are becoming increasingly global.  They say that the number of IDE applications and submissions for marketing authorization supported by ‘OUS clinical trials’ has increased in recent years and it is likely to continue increasing in the future.  They also say that this increasing globalization of clinical trials presents challenges to both US and foreign regulators. Among the challenges are constraints in resources that have an impact the number of foreign clinical site inspections and unnecessary duplication of clinical studies and administrative burdens.

Another proposed change acknowledges Section 1123 the FDA Safety and Innovation Act (FDASIA) of 2012,  Here, the FDA was required to accept data from clinical investigations conducted outside the US as long as the data were collected according to acceptable good clinical practice. While the FDA said it had a “longstanding” approach to accepting these types of data, FDASIA served to codify the practice into law and called on the FDA to clarify the processes by which the data could be accepted.

Thus an Either/Or Approach is indicated in its guidance document. Either a company’s clinical trials conducted outside the US meet federal human subject protection requirements exactly, or they meet local standards, which a company must show are either equal to or greater than US requirements for human protection under the Declaration of Helsinki (1983 version). In addition, the FDA’s guidance addressed what it calls “valid scientific evidence” – this is evidence from what the FDA defines as “well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts and reports of significant human experience with a marketed device.” Should the FDA determine that the OUS data constitute valid scientific evidence, under its code 21 CFR 860.7, then the OUS data can be used to support clearance or approval of the application, say the FDA. Sponsors intending to initiate or rely on an already-conducted OUS data should “seek input from the relevant Center for Devices and Radiological Health (CDRH) or Center for Biologics Evaluation and Research (CBER) review division at the earliest stage possible using the Pre-Submission process,” it adds.

Given all this, one might ask what factors sponsors should take into account when assessing whether they can rely on data obtained from studies conducted in countries other than the US. The FDA says that there are three main considerations:

• Are there differences in clinical conditions which might affect the standard of care afforded to a patient?
• Are there differences in the populations being studied, which might preclude the data from being extrapolated to US patients?
• Are there differences in regulatory requirements which might cause the study to fail to meet US requirements?

If readers require further insight into these considerations, seven examples are given in the 15 page draft document (1) of issues that can arise when using clinical data from device studies collected OUS to support FDA regulatory decisions. How the FDA and sponsors may seek to resolve such issues and the likely review outcomes are also mentioned.

Clearly from all this, medical device companies or other researchers aiming to conduct important or pivotal studies in countries other than (or in addition to) the US wanting FDA-standard data – and, in certain areas of the globe, there are considerable advantages in ease of set up, speed of recruitment as well as significant cost benefits without any sacrifice in data quality – should use a reputable Clinical Research Organisation well versed in all regulatory issues with well GCP-trained sites to ensure that all appropriate study standards meet or exceed those of the FDA and other regulatory bodies.

These new guidelines are currently published as a draft for the time being, with the FDA accepting comments until 20 July this year.

1. ‘Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States’ http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/UCM443133.pdf?source=govdelivery&utm_medium= email&utm _ source = govdelivery
2. ‘Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices’
   https://www.federalregister.gov/articles/2013/02/25/2013-04201/human-subject-protection-acceptance-of-data-from-clinical-studies-for-medical-devices