Acceptance of Foreign Clinical Trial Data

Guideline Title:

Acceptance of Foreign Clinical Trial Data

Status:

Finalized

Date of Guidance:

June 1998

Organizations Releasing Guidance:

Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH)

Link to the Guidance:

http://www.fda.gov/RegulatoryInformation/Guidances/ucm126426.htm

Target Audience:

Clinical investigators and Internal Review Boards (IRBs)

Small and large biomedical/pharmaceutical companies doing research and development and/or manufacturing of drugs, biologics, or medical devices outside of the United States (U.S.)

Laws and Regulations Referenced:

21 CFR part 312 IND

21 CFR 312.120(c)(1), Foreign clinical studies not conducted under an IND
21 CFR part 812, IDE
21 CFR 814.15(a) and (b), Research conducted outside the United States

Definitions:
BLA: a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.
Declaration of Helsinki: An international agreement pertaining to ethics in research on humans.
Evidence-based science: Definition debatable. Here, results are based on hypothesis testing, with quantifiable outcomes and peer review
Foreign clinical data: results gathered from studies outside the United States
Guidance: Formal advice or regulation (not a law). Here, given by a competent authority (FDA).
Good Clinical Practices (GCP) ICH E6: A guidance for the pharmaceutical industry published by FDA and agreed upon by the U.S., Japan, and Europe during the International Conference on Harmonisation (ICH E6).
Human subject: A person participating in a study or clinical trial
IDE: Investigation device exemption. Allows shipment of experimental devices without the need to be tested as normally required/
IND: Investigational new drug application. Request submitted to FDA for permission to investigate a new drug in humans.
Investigator: An individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.
Informed consent: A document with the information FDA and IRBs consider necessary to present to potential subjects of a clinicat trial. Subjects must understand the contents and willingly sign the consent form before being included in the study.
IRB: Institutional Review Board. Members of this board address ethical questions of a proposed study and give approval (or deny it) for the initiation of a study.
NDA: New drug application. Request for approval of a new drug to be released on the interstate market after conducting clinical trials.
PMA: Premarketing approval. Approval needed before releasing a medical device on the market.

Background:

In the current economic climate, foreign drug development and manufacturing activity has been increasing rapidly. American pharmaceutical companies, in an effort to save money, have turned to offshoring (moving manufacturing to foreign countries). In addition, foreign countries conducting their own clinical trials are applying for INDs, NDAs, IDEs, PMAs and BLAs using their own data. This guidance, providing a standardized methodology for obtaining FDA acceptance of foreign clinical trial data, was implemented by FDA in order to address the questions of scientific validity, good conduct of clinical trials, protection of human subjects, and application to the population in the United States.

Summary:

This guidance states the criteria for acceptance of foreign clinical trial data to be used to support PMA, IND, NDA, IDE and BLA applications. Under 21CFR 312 IND, these approvals are subject to FDA informed consent and IRB requirements. To be accepted, the clinical trial must provide protection to human subjects (in accordance with the Declaration of Helsinki or local standards, whichever ensures the most protection). The trial must have been conducted in accordance with Good Clinical Practices (ICH E6), ensuring a level of validity agreed upon by the countries involved (the U.S.A., Japan, and Europe). The investigators must be recognized as competent, and results must be based on valid evidence-based science. These data are subject to FDA audits. Finally, the data must be applicable to the population and medical practices in the U.S. If all these criteria are met, the foreign data may be submitted for acceptance as support for FDA marketing applications.

Resulting Recommendations:

For FDA approval:

·        Trial must be in accordance with the Declaration of Helsinki or local standards, whichever ensures the most protection to human subjects

·        Trial must be in accordance with Good Clinical Practices (GCP), ICH E6

·        Clinical investigators must have recognized competence

·        Results must be evidence based and valid

·        Results of trial must be applicable to the population and medical practices in the United States

             (Kumar, 2009)

Rationale:

As foreign activity in drug development and manufacturing has been increasing (more than 50% of INDs come from sites in foreign countries, more than 40% of investigators are non U.S. citizens, Kumar, 2009) and marketing applications in the U.S. have, in turn, been more numerous, a standard methodology with clear criteria was needed to help investigators and review boards ensure good conduct of foreign clinical trials and to streamline the drug development process which was hindered due to differing practices and study populations. By following this guidance, foreign clinical trial data can be evaluated more easily by competent authorities. New drugs, biologics, and medical devices can obtain approval in less time and at a substantially lower cost for small and large companies worldwide.  

Impact:

Providing an FDA-approved methodology for acceptance of foreign clinical trial data has a substantial worldwide financial impact on small manufacturers (savings of thousands of dollars) and large companies (savings of millions of dollars). This is especially advantageous for large global pharmaceutical companies who develop and manufacture drugs. (Biomedical Marketing Newsletter, 2001) Investigators can now refer to the guidance when designing their studies. IRB members also have a reference on which they can base their decisions. Ultimately, the general public benefits from this streamlining of the drug-approval process, as medicines become more readily available.