Jill Wechsler
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Just when Food and Drug Administration officials thought they could relax a little after months debating legislation to ensure
safe drug use, federal investigators leveled charges that agency oversight of clinical research is weak, disorganized, and
thus unable to ensure the safety of clinical research participants. This criticism came from the Office of the Inspector General
(OIG) in the Department of Health and Human Services (HHS), which has called repeatedly over the past decade for stronger
efforts to monitor clinical research and to take action against rule violators. Sen. Charles Grassley (R-Iowa), who requested
the OIG investigation as part of his campaign to uncover FDA malfeasance, promised to keep a close watch over how FDA implements
the OIG recommendations.
The OIG complains that FDA cannot identify all ongoing clinical trials, their associated trial sites or Institutional Review
Boards (IRBs) overseeing the research. The main reason is that the agency lacks an efficient information system for tracking
clinical research activity, site inspections, and resulting corrective actions.
Due to these inefficiencies as well as limited resources, FDA inspects less than 1% of relevant clinical trials. The OIG estimates
that from 2000 to 2005, FDA was charged with overseeing some 350,000 trial sites involved in more than 15,000 clinical research
programs for drugs and medical devices registered with FDA. However, the agency inspected only 2855 sites during this period,
ranging from 633 BIMO inspections in 2001 to 854 inspections in 2003.
Similarly, FDA inspected less than 300 Institutional Review Boards (IRBs) each year, partly because the agency has no complete
IRB database and thus cannot identify all review boards evaluating clinical trials for regulated products. FDA is working
with the HHS' Office of Human Research Protections (OHRP) to establish a mandatory system for registering all IRBs. The OHRP
database already lists more than 3500 review boards, primarily those at research organizations that receive National Institutes
of Health (NIH) grants or other federal funding and have to register their IRBs as part of the federal "assurance process."
FDA backs IRB registration as a way to improve agency communication with these organizations. The OIG report [OEI-01-06-00160 available at http://www.oig.hhs.gov/] is the latest in a series of investigations into FDA's bioresearch monitoring (BIMO) program. Back in 1998, the OIG issued
reports criticizing FDA's ability to ensure that IRBs appropriately monitor research under their jurisdiction. Another investigation
in 2000 documented weaknesses in FDA's clinical trial oversight program. The OIG is currently assessing how efficiently FDA
disciplines clinical investigators charged with research misconduct plus how well the agency and sponsors can monitor financial
conflicts of interest of clinical investigators.
Coordinating data
FDA established a Human Subject Protection/Bioresearch Monitoring Council in 2006 to better coordinate and streamline the
agency's diverse BIMO program, partly in response to such criticism. The agency also has been clarifying research policies
through the publication of several new guidances on timely research activities.
But the main problem, according to OIG, is that FDA needs a centralized database of all clinical trials involving drugs, biologics,
and medical devices to better coordinate research oversight. FDA currently has six different databases collecting information
on BIMO inspections for different Centers, as well as one in the Office of Regional Affairs, which manages the inspection
field force. These systems collect different kinds of information, using different formats and definitions, which makes it
difficult to coordinate inspections and track responses to citations.
In addition, the OIG criticizes FDA Centers for frequently reclassifying field recommendations for corrective action. The
result is that the Centers often decide that an inspection subject may make promised corrective actions instead of receiving
a warning letter. And when FDA Centers do send out warning letters, they often cannot determine whether a site takes corrective
action.
Another factor undermining FDA BIMO enforcement is the agency's limited oversight authority. FDA rules governing clinical
trials apply to sponsors and investigators, but not to clinical trial support staff that now play a large role in implementing
studies and dealing with participants. And FDA policies do not extend to foreign study sites, which now produce more than
20% of clinical trial data submitted to the agency. FDA investigators do visit some foreign sites to ensure data integrity,
but have little authority over patient protection issues.
