OIG Report Shows Increasing Use of Foreign Clinical Trials in Marketing Applications (and Challenges for the FDA)

There are no foreign lands.  It is the traveler only who is foreign.

Robert Louis Stevenson

Global.  That’s one of the buzz words/ideas that has gripped modern drug development.  In particular, there is a notion that foreign countries represent some unblemished Eden where clinical trials can be run cheaper and faster than in the “traditional markets”…namely North America and Western Europe.

There is certainly less competition for patients in some foreign countries; this can ease the primary rate-limiter for most trials (enrollment).  Costs can be cheaper as well (if they’re not, you probably took the wrong person to negotiate for you).  But, of course, nothing is perfect.  Can trials be run in compliance with GCP?  Yes, of course, but you’ll need to be extra-vigilant.  Can there be unexpected, or just plain baffling, bureaucratic hurdles?  Let’s just say that if you’ve managed global trials, you’re already familiar with the concept behind the axiom, “The grass is always greener…”

If you’re been in drug development for a while, you won’t be surprised to hear that the FDA receives a lot of foreign clinical trial data in marketing applications.  But how much is “a lot”?

The Office of Inspector General (OIG) recently published a report about the amount of foreign clinical trial data in marketing applications and the FDA’s challenges with monitoring and inspecting foreign clinical trials.  The report is titled “Challenges To FDA’s Ability To Monitor And Inspect Foreign Clinical Trials” and it examined clinical trial data from all marketing applications (NDAs, BLAs, and efficacy supplements) for products approved in FY 2008.  OIG had three primary findings and three recommendations:

Primary findings:

  1. In FY 2008, sponsors relied heavily on data from foreign clinical trials to support their marketing applications for drugs and biologics.
    1. 80% of approved marketing applications for drugs and biologics contained data from foreign clinical trials
    2. >50% of all clinical trial subjects and sites were located outside the United States
    3. Western Europe accounted for most foreign clinical trial subjects and sites Reliance on foreign clinical trials for FDA-regulated drugs and biologics appears likely to grow (no surprise!)
  2. FDA inspected clinical investigators at less than 1 percent of foreign sites.
    1. FDA inspected clinical investigators at few clinical trial sites overall (1.2% of domestic clinical trial sites and 0.7% percent of foreign clinical trial sites)
    2. FDA inspections targeted clinical investigators at domestic sites and original applications
  3. Challenges to conducting foreign inspections and data limitations inhibit FDA’s ability to monitor foreign clinical trials.
    1. FDA is unaware of some ongoing, early-phase foreign clinical trials
    2. Logistical challenges complicate foreign inspections
    3. Sponsors submitted clinical trial information in a nonstandard format
    4. FDA was unable to account for all clinical trial information (FDA was unable to provide detailed clinical trial data for 29 of the 129 applications within [the] review. FDA was unable to locate any portion of 8 of these 29 applications. All eight applications were paper.)

A few comments here:  1a) 80% is a little higher than I would have guessed.  Furthermore, remember that this is 2008 data which relied on studies conducted years before.  That number is only going to go up up up; 3a) I’ve seen some people try to make some hay out of this and accuse the FDA of dropping the ball, but, seriously, the FDA cannot reasonably be expected to be aware of all clinical trials going on in the world; 3c) Working at a CRO allows me to see a wide variety of sponsor formats.  Calling some of them ‘nonstandard’ would be generous; 3d) What?

OIG Recommendations (in full):

  1. FDA should require standardized electronic clinical trial data and create an internal database.
    1. Requiring sponsors to submit their clinical trial data in a standardized electronic format would help ensure that reviewers had all necessary information from sponsors to effectively analyze the data, enable FDA to create an internal database to systematically cull clinical trial information, and enable FDA to more effectively select sites for inspection and meet its review timelines.
  2. FDA should monitor trends in foreign clinical trials not conducted under INDs and, if necessary, take steps to encourage sponsors to file INDs.
    1. As sponsors submit future marketing applications with the results of foreign clinical trials that were not conducted under INDs, FDA should assess whether enrolled subjects were at additional risk and whether clinical trial data collected were both accurate and reliable. Should FDA determine that clinical trials not conducted under INDs compromised the rights, safety, and well-being of subjects or the integrity of the data submitted by sponsors, it should consider taking steps to encourage sponsors to voluntarily consult with FDA on their clinical trial protocols or submit INDs to the agency. FDA could also explore providing incentives to promote these, if it deems them appropriate.
  3. FDA should continue to explore ways to expand its oversight of foreign clinical trials. To improve its oversight of foreign clinical trials, FDA could take the following additional actions:
    1. Continue to develop inspectional agreements with foreign regulatory bodies. By sharing past inspection details as well as future plans, FDA would be better able to maximize its resources allocated to inspections of foreign clinical trial sites. FDA’s recent agreement with the European Medicines Agency is a positive step for the agency to extend its oversight capability outside the United States.
    2. Inspect clinical trials in more countries. FDA could target clinical trials in more countries, such as those in countries that the agency has not previously inspected or where Good Clinical Practice standards have only recently been adopted.
    3. Look to new models of oversight. FDA could explore other oversight models, such as a quality risk management approach, to oversee clinical trials.

The recommendations are more than reasonable and the FDA agreed with all of them (see Appendix E of the report for the full FDA response).

Speaking of recommendations, I recommend reading the full report; there are a lot of crunchable data within.  However, allow me to end with a graph and a figure from the report for visual consumption and consideration:

Graph 2: Average Number of Subjects per Foreign Site Contrasted With Percentage of Foreign Subjects and Sites by Region for FDA Marketing Applications Approved in FY 2008

Click to view full size image.

Figure D-1: Map of Subjects and Inspections per Country

Click to view full size image.

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