Many, if not most, medical device companies perform pilot clinical studies outside of the U.S. Cost reductions, avoiding a protracted FDA Investigational Device Exemption (IDE) approval process, and the ability to make design changes during the study without continual IDE amendments are the leading reasons to perform early studies outside the U.S (OUS).
A company can clearly save some money by performing an OUS clinical trial mainly due to the reduced hospital, physician and investigator, diagnostic exam, and operating room expenses. One of the biggest drivers in cost, however, is the Clinical Research Organization (CRO) that conducts study monitoring, site management and quality assurance. Although it may be more likely to find a lower cost CRO in some foreign countries, the quality of service may be commensurate with their pay, and managing cultural and language issues adds measurable cost in not just money, but time, output, and headaches. Additionally, translation of labeling and regulatory filings adds expense, along with travel. So, cost alone will probably not be reason to go offshore.
The IDE process is highly dependent upon the indication and device characteristics, so the impact on pilot study location should be evaluated on a case-by-case basis. Every group and review team at the FDA has its own distinct personality, with some groups being notoriously difficult and others having much more collaborative personnel. On the same project, I have experienced a 180 difference in outcomes based on a change to the FDA review team leader and medical adviser. On one particular project, the original team suggested returning to the FDA with 6-month data, while a change in the team personnel led to a requirement of a 1-year report before expanding clinical study in the U.S. The FDA team make-up directly influences review time, which could be the difference between a 30-day IDE approval and a laborious 6-month or longer back-and-forth.
A pre-IDE meeting is an FDA process for gaining informal direction (i.e. the FDA is not bound to any commitments) and can be very productive when the review team is experienced and understands risk-benefit. A pre-IDE meeting with a poor FDA review team, unfortunately, can cause more harm than good. That said; if you will eventually be conducting a U.S. pivotal clinical trial, consider scheduling a pre-IDE meeting to gain feedback on your study design. Although the FDA will not be approving the protocol, a pre-IDE meeting is your only opportunity to proactively address FDA concerns that could negatively affect their acceptance of the data.
Perhaps, the most significant reason to go offshore is flexibility in making design changes. Pilot studies can be a tremendous tool for refining your design and gaining insights with various iterations. Many foreign ministries of health (FDA counterparts) do not require regulatory filing amendments unless the design change increases safety risk. For a U.S. study, however, if the design change affects form, fit, or function, it is prudent to file an IDE amendment prior to implementation. Regrettably, every amendment is a minimum 30-day review, with more likely a second round for answering questions and making required documentation changes. Thus, design changes in an IDE study can easily have a 5-month impact.
So, maybe the question is ’why ever do a U.S. pilot study?’ There is always the risk that the FDA will not accept your OUS data regardless of any pre-IDE discussions and there are clearly some pitfalls. Additionally, for devices that don’t require a clinical trial for Pre-market Approval (PMA), a U.S. marketing clinical study may be more representative of your target population and users. The point is not to exclude a U.S. Pilot study pathway, but to think strategically about early clinical study design and understand that experienced OUS sites and investigators abound in countries with a track record for efficient regulatory processes.
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