On a recent monitoring visit a Research Coordinator was inquiring about a Sponsor’s international research sites and if there were any specific policies on accepting clinical data from foreign/non-U.S. clinical sites. For this particular study the Research Coordinator expressed interest on how these sites support a premarket submission study conducted in the United States.
Section 569B of the Federal Food, Drug, and Cosmetic Act states that “In determining whether to approve, license, or clear a drug or device pursuant to an application submitted under this chapter, the Secretary shall accept data from clinical investigations conducted outside of the United States, including the European Union, if the applicant demonstrates that such data are adequate under applicable standards to support approval, licensure, or clearance of the drug or device in the United States.” In other words, any data obtained from outside of the United States for a clinical study will be held to the same standards as that data obtained within the U.S.
As clinical research is becoming more of a global entity an increased number of multinational clinical studies are being conducted. In discussions with the Research Coordinator, I referred to an FDA Guidance document from April 2015 to describe considerations that the FDA utilizes to verify scientifically valid clinical data and special recommendations the FDA provide sponsors to assist in ensuring the data is adequate and applicable under the FDA standards.
Clinical trials in support of a marketing application in the U.S. may include foreign clinical studies. The FDA sites specific challenges in using data derived from foreign countries. Some examples include:
- Differences in study population and intended US patient population
- Differences in disease characteristics
- Varying Treatment Standards
- Disparities in Regulatory Standards
- Language barriers with contracts and written protocols
While some of the above pose challenges to a clinical study, one can also see how these variances in patient population and disease states may prove advantageous in broadening a sponsor’s data pool while maintaining the specified intended use proposed in a protocol.
After reviewing the guidance documentation, we went directly to the regulations. The FDA has long accepted data in support of device submissions from outside of the United States.
- 21 CFR 814.15(a) states “A study conducted outside the United States submitted in support of a PMA and conducted under an IDE shall comply with part 812. A study conducted outside the United States submitted in support of a PMA and not conducted under an IDE shall comply with the provisions in paragraph (b) or (c)”.
- 21FR 814.15 (b) indicates “FDA will accept studies submitted in support of a PMA which have been conducted outside the United States and begun on or after November 19, 1986, if the data are valid and the investigator has conducted the studies in conformance with the “Declaration of Helsinki” or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects. If the standards of the country are used, the applicant shall state in detail any differences between those standards and the “Declaration of Helsinki” and explain why they offer greater protection to the human subjects.”
Regardless of where the studies are conducted, it is the role of the FDA regulators to conduct inspections to ensure the safety, efficacy, and ethical consideration of the trials. Some considerations that the FDA will take into account for an International Inspection include only foreign data being submitted to support an application, as well as insufficient or conflicting domestic and foreign data. In addition any suspicion of fraud, scientific misconduct, or violations to human subject safety or welfare would likely cause site to be audited.
What benefits or potential pitfalls do you think a research study may face when selecting both U.S. and foreign research sites? Please add your comments below.
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