Two major factors drive clients to consider running trials in foreign countries – cost and recruitment. The question we often get is: can we use the data from such trials in a US submission? The answer is: quite possibly. I won’t address the conduct of supporting trials in foreign countries, rather, this post addresses the conduct of studies in foreign countries to gather data for US FDA approval.
Legally, FDA has the authority to accept foreign data as the sole basis for marketing approval. CFR 314.106(b) sets out these requirements:
- The foreign data are applicable to the U.S. population and U.S. medical practice
- the studies have been performed by clinical investigators of recognized competence; and
- the data may be consider valid…
FDA may reject an NDA filing if there is “inadequate evaluation for safety and/or effectiveness of the population intended to use the drug, including pertinent subsets, such as gender, age, and racial subsets.” (CFR 314.101(d)(3)).
FDA will decide at review time whether the foreign data meet the criteria above. Some of the factors the reviewers will use to decide if the foreign data are applicable to the US population and US medical practice are found in ICH E5 Ethnic Factors in the Acceptibility of Foreign Clinical Data and FDA’s Guidance on E5. A key concept of E5 is that data from one region must be extrapolated to another region and that significant gaps may be addressed by conducting bridging studies in the reviewing region.
ICH E5 defines ethnic factors as arising from two sources, extrinsic and intrinsic.
- Extrinsic Ethnic Factors – Factors associated with environmental and culture in which a person resides. These factors tend to be less genetically, more culturally and behaviorally determined.
- Intrinsic Ethnic Factors– Factors that help to define and identify a sub-population and may influence the ability to extrapolate.
Extrinsic tend to not be directly related to a drug while intrinsic are heavily drug dependent. No bridging study would be needed if:
- the drug is ethnically insensitive and extrinsic factors are similar
- the drug is ethnically sensitive but the two regions are ethnically similar and there is sufficient clinical experience with pharmacologically related compounds
The second point above is very useful in 505(b)(2) submissions (also, this provison explains why the FDA is less likely to refuse data from European studies – historically, FDA considers the population of the US to closely mirror Europe). We would look for data from RLD or similar drugs in global trials to justify the acceptance of foreign trial data without further bridging studies. Drugs that meet the following factors would tend to be less sensitive to ethnic factors:
- Linear pharmacokinetics (pK)
- A flat pharmacodynamic (PD) (effect-concentration) curve for both efficacy and safety in the range of the recommended dosage and dose regimen (this may mean that the drug is well-tolerated)
- A wide therapeutic dose range (again, possibly an indicator of good tolerability)
- Minimal metabolism or metabolism distributed among multiple pathways
- High bioavailability, thus less susceptibility to dietary absorption effects
- Low potential for protein binding
- Little potential for drug-drug, drug-diet and drug-disease interactions
- Nonsystemic mode of action
from NOTE FOR GUIDANCE ON ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA, ICH E5, Appendix D