International Clinical Trials and the Challenges of FDA Oversight

The Department of Health and Human Services Office of Inspector General (OIG) recently released a report [PDF 1.8 MB] raising doubts about the FDA’s capacity to monitor the safety of clinical trials conducted in foreign countries. According to the report, the FDA needs to:

1. Improve electronic reporting: many international trials reported safety and human subjects data in database-unfriendly formats;
2. Increase the monitoring of foreign clinical trials: the FDA is 16 times less likely to inspect foreign research sites than domestic sites;
3. Look for new ways to expand FDA oversight of foreign clinical trials, including: building new agreements with national regulatory agencies and creating new oversight programs.

While the FDA agreed with all three OIG recommendations, the agency may not have the money and staff to do the job. Inspecting research sites in other countries is logistically difficult and expensive. (According to one FDA source, inspections cost “about $40,000 each”.) With a growing number of multisite trials (with subjects enrolled in different cities, countries and regions), the cost of ensuring the safety of international medical research is indeed a high one. On the other hand, the benefits of conducting trials at non-U.S. sites are enticing. In addition to easier recruitment, diverse populations, and lower financial overhead, the Association of Clinical Research Organizations (ACRO) press release insists: “globalized trials can reduce development time by more than half”. With these and other incentives, the percent of international clinical trials has doubled in the last decade. As would be expected, while the number of FDA regulated investigators in non-U.S. countries has increased by 15% each year since 2002, the number of non-U.S. subjects enrolled in international clinical trials has also grown. In the year 2008, 78% of all human subjects participating in FDA regulated clinical trials were enrolled in foreign sites.

The impact of the OIG’s report may lead to new or increased scrutiny of how these clinical trials are conducted and regulated. While some of this increased scrutiny may come from the FDA, other government agencies, including the Department of Justice (DOJ) may get involved. An advisory [PDF 532 KB] written by Kirk Ogrosky (the former Deputy Chief for Health Care Fraud in the DOJ) and attorneys at the firm of Arnold & Porter, encourages researchers to: prepare for heightened FDA inspections; strengthen internal oversight of CROs; and ensure that research-related payments “pass muster” under anticorruption laws, including the FCPA. According to Arnold & Porter, the DOJ will be interested in payments that “may have been used as an incentive to inappropriately increase subject enrollment” and will examine “differences in payments among investigators in varying locations, and between sites overseen by … local CROs”.

For its part, ACRO stands behind a July 2009 report it commissioned on the ethics and safety of international clinical trials. In addition to restating its findings, ACRO responds to the OIG report by calling for: fully funded FDA oversight, improved research infrastructure, and universal protection of human subjects, including by the standards of the International Conference on Harmonisation’s Guideline for Good Clinical Practice [E6(R1) – PDF 380 KB].

In an editorial published in The Washington Examiner, two ethicists expressed similar confidence in the safety of international research, but worried that the public might miss the fact that a disproportionately large portion of clinical research is currently conducted in the U.S. In their assessment, to effectively and fairly address global health disparities, the number of international clinical trials should (by necessity) increase in the coming years.

In the absence, however, a simultaneous and proportional increase in FDA and other oversight, the risk that foreign clinical trials may be conducted in an unsafe or unscrupulous manner will remain unknown. At the very least (rightly or wrongly), without transparent oversight, public perception may increasingly reflect the sentiments of Adil E. Shamoo in The New York Times. Shamoo, on thinking about the “potential problems” of accountability in international research and the allure for CROs, noted: “There is less liability, patient recruitment is far easier, the concept of informed consent is not well established, and it’s cheaper.”

References:

ACRO responds to HHS report on FDA inspection of foreign clinical trials. Association of Clinical Research Organizations. 2010 Jun 22. Available from: http://www.acrohealth.org/acro-responds-to-hhs-report-on-fda-inspection-of-foreign-clinical-trials.html

Clark, Todd D. The case for globalization: ethical and business considerations in clinical research. Value of Insight Consulting [Commissioned by Association of Clinical Research Organizations]. 2009 July 21. Available from: http://www.acrohealth.org/globalization-white-paper.html

Harris, Gardener. Concern over foreign trials for drugs sold in U.S. The New York Times. 2010 Jun 21. Available from: http://www.nytimes.com/2010/06/22/health/research/22trial.html

ICH. Guideline for good clinical practice. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 1996 Jun 10. E6(R1). Available from: http://www.ich.org/LOB/media/MEDIA482.pdf

Malani, Anup and Tomas J. Philipson. Push for more trials may hurt patients. The Washington Examiner. 2010 Jul 21. Available from: http://www.washingtonexaminer.com/opinion/columns/Push-for-more-clinical-trials-may-hurt-patients-1002114-98875969.html

Office of the Inspector General, HHS. Challenges to FDA’s ability to monitor and inspect foreign clinical trials. Department of Health and Human Services (US); 2010 Jun. 50 p. Report No.: OEI-01-08-00510. Available from: http://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf

Ogrosky, Kirk and Arnold & Porter. Heightened scrutiny of foreign clinical trials. Arnold & Porter, LLP. 2010 Jul 12. Available from: http://www.arnoldporter.com/resources/documents/Advisory-Heightened_Scrutiny_of_Foreign_Clinical_Trials_071210.pdf

Other Research Ethics News

Jonathan D. Moreno. One Small Step for Embryonic Stem Cells: FDA approves first clinical trial for stem cell treatment. Science Progress. August 4, 2010.

Janet Moore. U is closer to a campuswide policy on business conflicts of interest. Star Tribune [Minneapolis-St. Paul, Minnesota]. August 4, 2010.

Elizabeth Cooney. Industry-funded drug trials more likely to report positive results, study finds. White Coat Notes. [The Boston Globe]. August 2, 2010.

Yojana Sharma. Conference agrees global science ethics code. SciDevNet. July 28, 2010.

Columbia Professor accused of research misconduct/fraud. GhanaWeb. July 21, 2010.

Benedict Carey. Studies halted at brain lab over impure injections. The New York Times. July 16, 2010.

Kathy D. Miller. Is mandatory biopsy in clinical trials justifiable? Medscape Today. July 13, 2010.

Gardiner Harris. Diabetes drug maker hid test data, files indicate. The New York Times. July 12, 2010.

David Glenn. Inside the Risky World of Drug-Trial ‘Guinea Pigs’. The Chronicle of Higher Education. July 11, 2010.

Meredith Wadman. Institute of Medicine weighs in on the ethics of post-market drug trials (Subtext: Avandia). The Great Beyond. July 9, 2010.

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