The US Food and Drug Administration’s record on drug safety has come under fire again, just one day after a bill giving the agency significant new powers in areas such as mandatory post-marketing studies and changes to the product labels was signed into law.

President George Bush gave the final nod to the Food and Drug Administration Amendments Act of 2007 on 27 September 20. The following day the FDA was in the docks again, this time over the frequency – or rather lack – of clinical trial site inspections under its Bioresearch Monitoring (BiMo) programme.

A report by the Department of Health and Human Services’ Office of Inspector General (OIG) found that the FDA had inspected fewer than 1% of clinical trial sites between the fiscal years (FYs) 2000 and 2005.

The bulk of these inspections were concerned with data integrity rather than the protection of clinical trial participants. And if the FDA did identify serious problems during an inspection, these were unlikely to result in enforcement action. Of the 348 BiMo inspections that warranted an official action indicated (OAI) classification in FY2000-2005, 70% (244) sought voluntary compliance through a warning letter while just 8% (26) prompted a disqualification letter and 1% (two) resulted in disqualification of data.

In line with previous OIG findings, the latest probe concluded that the FDA did not have a mechanism to identify all clinical trials or the Institutional Review Boards (IRBs) that approve, monitor and review research involving human subjects. Nor did the agency keep a comprehensive database for tracking its inspections of clinical trials.

“Because FDA does not maintain a clinical trial registry, it is unable to identify all ongoing clinical trials and their associated trial sites,” the report stated. “Further, because FDA does not maintain an IRB registry, it is unable to identify all IRBs. Even though FDA maintains six databases to track BiMo inspections, none includes complete information needed to track all such inspections.”

“The FDA has no way to keep track of the number of clinical trials being done every year, who does them, who pays for them or even how many people are involved as subjects,” commented Dr Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania. “This is beyond belief since the government agencies responsible for monitoring research with animals collect exactly that data every year. How can it be that we know how many pigs, frogs, rats and monkeys are used in research and who uses them without knowing what is going on with respect to human beings?”

Due to the paucity of FDA data, the OIG used the number of investigational new drug applications (INDs) and investigational device exemptions (IDEs) received by the Center for Drug Evaluation and Research (CDER) and other review centres as well as estimates from the clinical trial registry maintained by the National Institutes of Health (NIH) to estimate the percentage of trial sites that BiMO inspections were reaching.

On this basis, the OIG calculated that the 15,268 INDs and IDEs submitted to the Centers in FY2000-2005 included some 350,000 trial sites, so the 2,855 BiMo site inspections recorded over the report period covered fewer than 1% of those sites.

Some 75% of BiMo inspections in FY2000-2005 were surveillance inspections, which “generally focus on verifying the clinical trial data that sponsors submitted with their new product applications”, the OIG noted. Moreover, most surveillance inspections target completed trials, so they “cannot ensure that sponsors, clinical investigators and IRBs are taking the necessary actions to protect human subjects during the trials”. The OIG also estimated that FDA centres “at most” inspected around 6% of IRBs each year, or fewer than 40% of all IRBs in the six-year report period.

Classifications downgraded

One finding highlighted by Republican Senator Charles Grassley, who had asked the OIG to review the FDA’s oversight of clinical trials, was that classifications of clinical trial inspections by the FDA’s Office of Regulatory Affairs and the its review centres were often inconsistent.

Specifically, between FY2000 and FY2005 CDER revised 68% of ORA’s OAI recommendations (the most serious classification) and the Center for Devices and Radiological Health revised 23% of these recommendations. In most cases the inspections were reclassified to voluntary action indicated (VAI), “a classification that neither requires the inspected entity to formally address violations the centre identified nor makes the classification publicly available”, the OIG pointed out.

“In other words,” added Senator Grassley, “the CDER often downgrades the seriousness of the clinical trial violation.”

The OIG’s report made the following recommendations for improvements to BiMo information systems and processes:

The FDA should:

- Develop a comprehensive internal database of clinical trials in order to more effectively identify and target ongoing studies for inspection.

- Create an IRB registry, which would allow the agency to target review boards more effectively for inspection.

- Create a cross-center database for comprehensive tracking of BiMo inspections.

- Establish a mechanism to provide feedback to BiMo investigators on their inspection reports and findings.

- Seek legal authority to provide “oversight that reflects current clinical trial practices”, taking in all stakeholders in the management and conduct of clinical studies.

The Food and Drug Administration Act of 2007 includes provisions to expand the NIH clinical trials registry to cover all ongoing clinical trials other than Phase I studies, not just those for serious or life-threatening conditions.

Broad mandate

The FDA concurred with four of the OIG’s recommendations but did not address the issue of providing feedback to BiMo inspectors. The agency also pointed out that the report focused “on only one component of human subject protection and bioresearch monitoring, namely inspections”.

Protecting human subjects was “a broad mandate and the programmes are numerous”, the FDA commented. “In fact, FDA believes the most important component of the BiMo programme in protecting human subjects is the protocol review. In order to ensure the highest degree of human subject protection, FDA carefully scrutinises all protocols submitted to the agency and will require sponsors to revise protocols as necessary, thus ensuring the greatest protection of human subjects before a clinical investigation even begins.”