In fiscal year 2008, 80% of marketing applications for drugs and biologics approved by the Food and Drug Administration (FDA) included data from clinical trials conducted outside the US.

Yet in the same year the FDA inspected only 0.7% of foreign clinical trial sites, a report by the US Department of Health and Human Services’ Office of Inspector General (OIG) has found. According to consumer group Public Citizen, the report “confirms some of the worst fears about the serious dangers of the escalating globalisation of human experimentation”.

It is estimated that 40-65% of clinical trials for FDA-regulated products are conducted outside the US, noted the OIG report on Challenges to FDA’s Ability to Monitor and Inspect Foreign Clinical Trials.

The benefits of moving trials abroad include lower costs in some countries or faster completion times for large studies. All the same, the OIG pointed out, critics have raised concerns about the increased prevalence of foreign clinical trials, particularly when they are conducted in developing countries.

Medical ethicists have qualms about the ability of local regulatory bodies and institutional review boards to monitor adequately data integrity and the protection of clinical trial participants’ rights and welfare. Other critics question the extent to which results from trials conducted in developing countries can be generalised to the US population.

The OIG reviewed all marketing applications for drugs and biologics approved by the FDA in fiscal year 2008 (FY 2008) that included clinical trial data. There were 129 applications in total and 121 of these (106 for drugs and 15 for biologics) contained enough information to determine whether sponsors had submitted foreign or domestic clinical trial data.

In all, 97 out of the 121 marketing applications (80.2%) contained some element of foreign clinical trial data. Sponsors filed 91 applications for drugs including at least one foreign clinical trial site, while nine of these applications contained exclusively foreign data. There were six marketing applications for biologics including at least one foreign clinical trial site, and one of these applications contained exclusively foreign data.

Subjects and sites

In terms of participants and locations, 77.6% of the 299,701 subjects recruited for clinical trials supporting FDA applications for drugs and biologics in FY 2008 were enrolled at foreign sites, while 54.3% of the 11,944 trial sites were foreign. Although the percentages of foreign trial sites used were similar for drugs and biologics (54.6% versus 49.7%), marketing applications for biologics showed a much higher proportion of subjects enrolled at foreign sites (86.9% versus 56.9% for drugs).

As the OIG pointed out, marketing applications for biologics often include “extremely large” clinical trials. For example, one trial in Sweden enrolled almost 83,000 subjects at 14 sites, which “partially explains the large difference in the number and percentage of foreign subjects in applications for biologics compared to drugs”.

Among the approved marketing applications relying on data from outside the US in FY 2008, Western Europe accounted by some distance for the highest proportion of both enrolled subjects (58%) and trial sites (60%). Central and South America contributed 26% of all enrollees in foreign clinical trials but only 7% of foreign trial sites. The average number of subjects enrolled per site in Central and South America was more than three times that in Western Europe.

Overall, the FDA inspected clinical investigators at 147 or 1.2% of trial sites for drug and biologic applications approved in FY 2008. That included 102 inspections at domestic sites – 1.9% of the US total – and 45 (0.7%) at foreign sites.

Trial sites were inspected in only 20 of the 72 countries identified in the OIG review. Some of the countries not inspected enrolled large numbers of subjects for clinical trials supporting FDA applications, such as Peru (13,628 subjects), Columbia (5,480) and Chile (4,949).

Moreover, the agency may be unaware of some ongoing early-phase clinical trials conducted outside the US, as these are increasingly pursued without filing of an investigational new drug (IND) application, the OIG notes, adding that current regulations allow sponsors to submit data from these trials in support of future US INDs or marketing applications.

Another area of concern highlighted in the report was that the FDA is unable to account for all clinical trial information in marketing applications, because files are missing or sponsors fail to provide details in study reports of site locations and subjects enrolled.

IOG recommendations

The OIG made a number of recommendations for improvements to the FDA’s system for overseeing foreign clinical trial data. These included:

- Requiring sponsors to submit clinical trial data in a standardised electronic format. This would “help ensure that reviewers had all necessary information from sponsors to effectively analyse 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”.

- Monitoring trends in foreign clinical trials not conducted under INDs and, if necessary, taking steps to encourage sponsors to file INDs or consult voluntarily with the FDA on trial protocols. “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”, the OIG said.
- Continuing to explore ways to expand FDA oversight of foreign clinical trials through:

- Further inspectional agreements with foreign regulatory bodies, such as the FDA’s recent arrangement with the European Medicines Agency.

- Inspecting clinical trials in more countries – for example, in those where the FDA has not previously inspected sites or where Good Clinical Practice standards have only recently been adopted.

- Looking at new models of oversight for clinical trials, such as a quality risk management approach.

According to the OIG, the FDA agrees with all three of these recommendations and says they are being addressed either through ongoing efforts or through new procedures in development. For example, the report noted, the agency is piloting a computer-based tool to select inspection sites based on risk factors unique to a particular clinical trial.

FDA has jurisdiction

The US industry association Pharmaceutical Research and Manufacturers of America (PhRMA) said it was important to remember the FDA had jurisdiction over clinical trials conducted in foreign countries for drugs approved or intended for approval in the US.

“The same strict regulatory standards apply to foreign trials as trials conducted domestically,” stated PhRMA senior vice president Ken Johnson. “Sponsors are typically in communication with the FDA throughout clinical trials – no matter where they are conducted.”

PhRMA member companies were also committed to adhering to Good Clinical practice (GCP) guidelines around the world, in line with the association’s Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results, Johnson added.

“In fact, PhRMA has conducted educational seminars and symposiums – at times, in conjunction with the FDA – in other countries to educate potential clinical trial principal investigators about Good Clinical Practices, ethics oversight by outside review boards, and the need to maintain the highest standards for data quality,” he noted.

The US-based Association of Clinical Research Organizsations (ACRO) said it supported the recommendations of the OIG report and had been “actively advocating for increased funding for the FDA’s Office of International Programs to provide the agency with sufficient resources to ensure research quality is maintained around the world”.

ACRO members were “global leaders” in adherence to the GCP principles set by the International Conference on Harmonisation, the association added. Moreover, contract research organisations trained research staff around the world in GCP principles, while “proof of compliance is required by drug regulators in every major pharmaceutical market”.

The association cited the findings of a report it published in July 2009, which concluded that globalisation of clinical trials could reduce drug development times by more than half while maintaining quality and safety. “ACRO will continue its efforts to collaborate with stakeholders around the world to enhance clinical development and encourage clinical research participation,” it stated.

Health threat

Public Citizen was not persuaded, though. “In addition to the increased dangers to human subjects in many countries because they have less adequate protections than in the United States, there are significant threats to the integrity of the data being generated from these experiments because of the decreased ability of FDA to monitor and inspect foreign sites”, commented Dr Sidney Wolfe, director of the organisation’s Health Research Group.

As a result, he claimed, “the quality of the data used by the FDA as a basis for approving the drugs being studied may well be flawed, resulting in dangerous, incorrect decisions to approve drugs, jeopardising the health of people in this country and elsewhere. Massive marketed use of drugs that possibly should not have been approved extends the dangers beyond the subjects of the clinical trials to the general public”.