Government Accountability Project

The Inspector General of the Department of Health and Human Services, Daniel R. Levinson, is issuing a report today, according to Gardiner Harris in The New York Times, finding that FDA approvals of ten medicines in the US in 2008 were based exclusively on clinical trials conducted abroad. The report found that, overall, fewer than one percent of the foreign trial sites were inspected by the FDA, that 80 percent of the drugs approved for sale in the US in 2008 were based at least in part on trials conducted abroad, and 78 percent of trial participants were enrolled at foreign sites.

These numbers may be shocking but should not be surprising. Last year GAP published a monograph titled “The ABCs of Drug Safety” (pdf) providing a “Roadmap for Conducting Credible Clinical Drug Trials and Protecting Drug Trial Participants.” Here is an excerpt from that report (please see report for citations):

a) Unaddressed Gap

The federal government only regulates clinical trial research that is under HHS or FDA oversight. Several pre-Phase I, Phase IV, and investigator-initiated trials do not fall under the control of either agency. State, local, or institutional research or health laws may provide some trial participant safeguards, but none of these laws or policies effectively protects all human subjects in all research in this country.

If research is eventually submitted as part of a drug application to the FDA, it must comply with federal human subject regulations. But, clinical trials are increasingly conducted abroad, “where oversight is slim and patients plentiful.” And, drug companies get the results they want:  One review found that 99 percent of controlled trials published in China gave the investigative drug the green light. This challenges credulity. The number of foreign clinical investigators seeking FDA approvals increased 16-fold during the 1990s.  San Petersburg (Florida) Times reporter Kris Hundley found that in the past three years, FDA had inspected only eight out of thousands of clinical trial sites in India.  Hundley writes: “In the burgeoning clinical trial business, says Amar Jesani, a doctor and medical ethicist in Mumbai, every layer of oversight is compromised by cash, and independent monitoring is nonexistent. He has resigned from supposedly independent ethics committees that rubber-stamp drug companies’ proposals and overrule any objections. Said Jesani: ‘We’re sitting on a time bomb that may explode at any time.’”

Unlike trials in U.S. studies, the FDA does not require animal testing prior to conducting human experiments abroad.  The IRB requirement is also waived.  Until recently, foreign studies need only have followed the World Medical Association’s Declaration of Helsinki, which the Trovan case (see A.1.c. State Statutory Whistleblower Protection Provisions & Common Law or Judicially-Created Remedies) illustrates is less than an ineffective safeguard.  But the FDA recently dropped even the requirement that foreign trials comply with the Helsinki guidelines.83  Not surprisingly, an HHS report concluded that “FDA cannot assure the same level of human subject protections in foreign trials as domestic ones.”

b) Caught in the Gap:  Research Subjects at Risk

Each year an estimated 40 percent of research studies, including pre-Phase I, Phase IV, and investigator-initiated trials, conducted in the U.S. are not regulated by the federal government. Over five million Americans participate in these unregulated studies. This gap in federal oversight raises significant public safety issues. Institutions are left with the burden of deciding whether or not to oversee unregulated research, and how extensively, if they decide to oversee this type of research.

c) Legal Gaps

Despite enacting the National Animal Welfare Act, which regulates all research conducted on animals, Congress has not yet enacted comparable legislation to protect all human subjects.

d) GAP Suggested Reform

GAP supports the National Bioethics Advisory Commission recommendation for a national system of oversight. We also agree with experts and advocates who have lobbied persistently for the passage of a National Human Subjects Protection Act to provide regulatory protection to all research subjects. We suggest that Congress enact legislation to cover all human subject research; alternatively, we encourage states to follow Maryland’s lead and enact laws that apply to all human research.

A critical tool that will assist in monitoring all human subject research or at least provide some transparency to current work – regulated or not – being conducted on humans is a more effective clinical trials registry.  The current registration system lacks accountability and quality assurance.  For example, the exact number of clinical trials currently being conducted worldwide cannot be quantified precisely. (For resources in researching clinical trials, see “Suggested Resources for Researching Clinical Trials, infra.)  Further, under the current system, a drug company could potentially conduct an unregistered trial and may never report the trial if the results were unsatisfactory.  This ability to only register or publish positive results in duplicative, wasteful research, and exposes research participants to dangers that could easily have been avoided with greater transparency.

One suggested solution is to establish a comprehensive registry. Each clinical trial initiated would be required to register and thereby even if study findings were not published, the trial itself would be made public. The registry should describe the main features of the study, such as outcome variables and study duration.  Theoretically, this global registry would enable physicians, scientists, and consumers to review both the unsuccessful and successful trials being conducted worldwide.   The Food and Drug Administration Modernization Act required the NIH to establish a registry of clinical trials. Registration on this site, clinicaltrials.gov, is voluntary unless the trial is a federally or privately funded experimental treatment for “serious or life-threatening diseases and conditions.”  This site is the largest registry in the world and has facilitated an increase in trial registration; yet, it lacks a critical component – results of the trials.

The World Health Organization (“WHO”) in 2004 began to assign all randomized controlled trials approved by the WHO Ethics Review Board an International Standard Randomized Controlled Trial Number (“ISRCTN”). Prominent medical organizations support this concept of a public, all- inclusive registry. The International Committee of Medical Journal Editors (“ICMJE”) requires all clinical trial, including Phase I, to be registered at their inception in an acceptable registry in order to be published in any of their member journals. ICMJE requires that even minimum data and Phase I (early toxicity) be registered, and the site must be publicly accessible at no charge and be managed by a not- for-profit organization. Results are not required.  Some pharmaceutical companies have their own registries that contain only their studies, governed by their own registry guidelines, which may post results.  The Pharmaceutical Research and Manufacturers of America (“PhRMA”) has its own results database called clinicalstudyresults.org, but this site notoriously draws favorable study results. The variety of registries forces potential research participants to search multiple web sites.  The inconsistency in both the kind and the quality of data reported result in potential participants attempting to compare and contrast inadequate and incomplete trial information.  Without a results database, quality and timely meta-analyses are unlikely.

Legislation addressing the registry and results database infrastructure is needed.  Public financing and monitoring of registration needs to be considered. Similarly, legislative reform should include the publication of all research protocols prior to the initiation of research and public dissemination of the results of all completed trials.  Penalties need to attach for non-compliance.  Congressional oversight is needed to ensure the FDA enforces registry and results database regulations, particularly in international contexts.  The FDA must also strengthen its regulations regarding international studies and partner with foreign governments to ensure the ethical conduct of clinical trials worldwide.

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Mark Cohen is Executive Director of the Government Accountability Project, the nation's leading whistleblower advocacy organization.