US marketing approval of drugs and devices by sole reliance on foreign (non-US) clinical data

Albeit some sponsors may seek to rely solely on foreign (non-US) clinical data as support for an Investigational Device Exemption (IDE), marketing authorisation of a device in the US or marketing authorisation of a drug* or biologic in the US. Section 569B of the Federal Food, Drug, and Cosmetic Act codifies FDA’s longstanding approach of accepting adequate, ethically derived and scientifically valid data irrespective of where the study is conducted.

However, certain challenges exist in using data derived from foreign studies of drugs or devices to support an FDA marketing authorisation. These challenges may include differences between the study population and the intended US patient population, difficulties in extrapolating from different endpoints used to support foreign (non-US) review standards and even differences in disease characteristics and treatment standards. The challenges may be of such a degree that the study is not adequate by itself to demonstrate that the drug or device, when used in the US in the intended US population, meets the applicable US statutory premarket review standards. Promoting greater clarity concerning FDA’s use of foreign (non-US) data will reduce unnecessary duplication, harmonise global clinical trial standards and promote public health and innovation.

Considerations when relying on foreign (non-US) clinical data for marketing approval of a drug or device:

Per 21 CFR 314.106 (for drugs) and 21 CFR 814.15 (for devices), an application based solely on foreign clinical data meeting US criteria for marketing approval may be approved if:

1. Foreign data are applicable to the US population and US medical practice
2. Studies have been performed by clinical investigators of recognised competence
3. FDA has validated trial data through on-site inspections or other appropriate means

These CFRs further state that FDA encourages applicants to meet with the FDA review divisions in a “pre-submission” meeting when approval is based solely on foreign data. It has been found to be in the best interest of sponsors from development cost and timely approval perspectives.

There are several considerations that sponsors of marketing applications for drugs and devices should think about and address as early in the drug or device development process as possible when seeking to rely on foreign clinical data in support of a drug or device submission. The key questions raised in these cases are:

• Do the foreign (non-US) human subject protection standards meet FDA’s applicable requirements?
• Are there differences between foreign (non-US) and US clinical conditions, regulatory expectations and/or study populations such that the data would not be sufficient to support the safety and/or effectiveness of the studied drug or device?

Some considerations relate to basic questions of study design and good clinical practice issues that can also arise in FDA’s review of studies conducted in the US. The 21 CFR 314.106 also notes that FDA will apply the evaluation of foreign data policy in a flexible manner according to the nature of the drug and the data being considered. ICH recommendations may be considered by the FDA reviewer for evaluating the foreign (non-US) clinical data for marketing approval of drugs. Prior to ICH E17, principles described in ICH E5, served as the basis for evaluation of foreign data. ICH E5 (Ethnic Factors in the Acceptability of Foreign Clinical Data) addresses primarily how development programs in one or two regions might support approval in another region. The primary objective of ICH E5 is to minimise duplicative clinical trials by outlining three steps (i.e., assessment of the data package, sensitivity to ethnic factors and bridging data package) to determine the acceptability of foreign data as the basis of a marketing application. ICH E5 recommends a framework for evaluating the impact of ethnic factors on the efficacy and safety of a drug at a particular dosage and dose regimen. Ethnic factors are defined as those factors relating to the genetic, physiologic (intrinsic) and the cultural and environmental (extrinsic) characteristics of a population.

Today, ICH E5 and ICH E17 should be used in tandem when designing and conducting Multiregional Clinical Trials (MRCTs). In 2017, ICH provided an additional guidance document discussing concurrent global registration strategies using MRCTs. This guidance reflected an emerging consensus that trials requiring international collaboration were preferred over single country trials. In ICH E17 (General Principles on the Planning and Design of MRCTs), importance is placed on the strategic use of MRCTs throughout all phases of drug development rather than conducting trials from single countries or limited regions.

In conclusion, by law, FDA has authority to approve the drug or device marketing authorisation applications based solely on foreign clinical data meeting US criteria for marketing approval, if stipulated requirements as discussed above are met.

If you are interested in submitting foreign data in support of a marketing application, contact the ICON Strategic Regulatory Services team for more information.

*All references to drugs in this blog include biological products which are a subset of drugs.

 

References

1. The Office of the Law Revision Counsel of the United States. Published June 25, 1938. Added July 9, 2012. Amended December. 13, 2016. Section 569B of Federal Food, Drug, and Cosmetic Act (FD&C Act) - 21 USC 360bbb-8b: Use of clinical investigation data from outside the United States. Accessed November 9, 2022.
2. The National Archives and Records Administration’s Office of the Federal Register. Updated November 7, 2022. 21 CFR 314.106 Foreign data. Accessed November 9, 2022.
3. The National Archives and Records Administration’s Office of the Federal Register. Updated November 7, 2022. 21 CFR 814.15 Research conducted outside the United States. Accessed November 9, 2022.
4. ICH. Published February 5, 1998. ICH HARMONISED TRIPARTITE GUIDELINE ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA Accessed November 9, 2022.
5. ICH. Published November 16, 2017. ICH HARMONISED GUIDELINE GENERAL PRINCIPLES FOR PLANNING AND DESIGN OF MULTI-REGIONAL CLINICAL TRIAL SE17. Accessed: November 9, 2022.