Conducting clinical trials outside the United States raises significant regulatory concerns that sponsors must evaluate before relying on foreign data to support a marketing approval submission or Investigational New Drug Application (IND) to the United States Food and Drug Administration (FDA). Any foreign clinical study not conducted under an IND must satisfy the requirements of 21 C.F.R. § 312.120, which conditions FDA's acceptance of such data on the study having been conducted in accordance with good clinical practice (GCP). The regulation further requires that the study be reviewed and approved by an independent ethics committee (IEC) prior to initiation, that informed consent was obtained and documented from each subject, and that FDA be able to validate the study data through an onsite inspection if the agency deems it necessary. Sponsors must also submit extensive supporting information to FDA, including a description of investigator qualifications, research facilities, how GCP compliance was ensured, and how the sponsor monitored the study. Failure to meet these conditions may result in FDA declining to accept the study data in support of an IND for a future trial or a marketing application.

A distinct and growing concern with foreign clinical trials involves the representativeness of trial populations. Under 21 C.F.R. § 314.106, marketing approval based solely on foreign clinical data requires that "the foreign data are applicable to the U.S. population and U.S. medical practice." FDA has increasingly emphasized that clinical trial populations should reflect the demographic, genetic, and ethnic diversity of the intended U.S. patient population. Differences in disease prevalence, healthcare system factors, dietary patterns, genetic ancestral backgrounds, and standard-of-care practices across countries can all impact the applicability of foreign trial results to U.S. patients. FDA has specifically recommended that sponsors enroll "a sufficient number of U.S. participants" and plan early-stage studies "in a population that reflects the diversity of the intended regions," in order to detect differential drug effects across subgroups. Where the trial population does not adequately represent the U.S. population, FDA may require sponsors to conduct additional U.S.-based studies or enroll supplemental subgroups of U.S. subjects, adding cost and delay to the development program.

Data integrity presents another critical challenge for clinical trials conducted abroad. FDA's capacity to inspect foreign sites has varied in recent years and the agency is attempting to adjust its surveillance strategies as more research and manufacturing take place overseas. FDA acknowledges that resource constraints limit the amount of foreign inspections the agency can conduct in its guidance, “FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND Frequently Asked Questions”. The limitations associated with foreign site surveillance create an environment in which data quality risks — including inadequate source document verification, deficiencies in monitoring, and potential fabrication or falsification of data — may go undetected. Additionally, sponsors face the challenge of ensuring that computerized systems used to collect and transmit clinical data at foreign sites meet FDA's expectations for audit trails, electronic signatures, and data security. To address challenges associated with foreign trial monitoring, FDA expanded its international GCP collaboration with the European Medicines Agency (EMA), the UK's MHRA, Japan's PMDA, and Health Canada to optimize regulatory resources and oversight. Nonetheless, the practical limitations on inspection capacity and the variability in regulatory frameworks across countries mean that sponsors bear a heightened burden of diligence at foreign sites.

The directors of FDA’s major medical products centers recently co-authored a post on the agency’s website discussing the challenges that foreign trials pose for agency staff. The post highlights agency concerns both with how multi-regional, non-US trials are used in product development and challenges associated with inspecting sites and verifying results. FDA outlined how it is addressing these concerns with more resources for bioresearch monitoring inspections, communications with sponsors, and additional training that is designed to help reviewers that are considering data from study sites that pose higher risk of data integrity concerns. The agency plans to pay increased attention to clinical studies and trial sites not subject to an IND to ensure that GCP were followed. FDA states that it will take efforts to ensure that product application reviewers only consider studies that properly satisfy the requirements discussed above. The post ends with FDA stating that these measures are not intended as a protectionism measure – FDA just wants sponsors to know that they are subject to inspection and evidentiary requirements wherever their trials are conducted.   

In light of regulatory, demographic, and data integrity concerns, sponsors contemplating foreign clinical development programs must undertake rigorous upfront planning and risk mitigation. Sponsors should engage with FDA early through pre-IND or pre-NDA meetings to discuss expectations for foreign data, particularly where approval or subsequent trials may be sought based solely or primarily on foreign clinical evidence. Site selection diligence, monitoring plans, and thorough investigator training programs are essential to demonstrate compliance with GCP and to satisfy regulatory requirements as a product’s clinical program progresses. Where foreign privacy laws or other local restrictions may impede FDA's ability to validate data through onsite inspection or direct access to records, sponsors should consider seeking waivers and collaborating with FDA on alternative validation procedures. Ultimately, conducting trials outside the United States requires a careful consideration of the heightened regulatory scrutiny and compliance risks that accompany reliance on foreign data.