The US Food and Drug Administration (FDA) has been called into question again after the release of a damning report, this time suggesting the agency is inadequate in its safety monitoring of clinical trials.
According to the report, released on Friday by the Office of Inspector General of the US Department of Health and Human Services (HHS), "weaknesses in the FDA's information systems and management processes hinder the agency's ability to oversee clinical trial inspections". This is not the first time the office has released a report citing such weaknesses and in recent times the FDA has been barraged with criticism about its safety monitoring systems. The new report found the FDA inspected just one per cent of clinical trial sites during the period between 2000 and 2005 - of the estimated 350,000 trial sites the FDA was believed to have inspected 2,855. Of the inspections that did take place, the report said they generally targeted completed trials and often focussed on verifying the quality of the data rather than human subject protection. The report also found there was a lack of follow ups on sites which had been issued with a warning letter after being classified as 'official action indicated' (OAI) for violations of regulatory significance. The FDA must re-inspect sites that have been sent a warning letter to ensure there are no repeat violations, but according to FDA data, which was noted to be inadequate by the report, the agency only conducted three follow-ups for every 100 inspections that were classified as OAI or voluntary action indicated (VAI). Other statistics showed that of the 348 OAIs classified by the FDA only 26 were disqualified from further clinical trials and only two had their data disqualified. Seventy per cent received a warning letter, relying heavily on voluntary compliance to correct regulatory violations. Many OAI recommendations were also downgraded to VAI, a classification where violations did not have to be formally addressed. The report also highlighted other areas where the FDA was found wanting. The agency did not maintain a clinical trial registry, so was unable to identify all ongoing trials and trial sites, and lacked an institutional review board registry, the report noted. The six databases used to track the Bioresearch Monitoring Programme (BiMo) inspections were incomplete in tracking information, the FDA showed a lack of co-ordination within its ranks, and FDA guidance and regulations were found to not reflect current clinical trial practice, the report added. The report also noted that although sponsors increasingly conducted clinical trials outside the US, the FDA had a limited authority over the control of foreign trials. "Data limitations hinder the FDA's ability to ensure that participants are protected from unreasonable risks," HHS inspector general Daniel Levinson said in a statement. "Accurate record-keeping is critical to maintaining the safety of clinical trial patients." Criticism over the safety monitoring of clinical trials is not new to the FDA. In 1998, the Office of Inspector General concluded institutional review boards "lacked the time and expertise to sufficiently monitor the research taking place under their jurisdiction", and in 2000 the office documented weaknesses in clinical trial oversight stating the BiMo programme lacked clear and specific guidelines and lacked an interest in human subject protection. But it is not just safety in clinical trials where the FDA has been attacked. Last month, an article was published in the journal Archives of Internal Medicine suggesting the existing post-marketing safety system "is not adequately protecting patients" following findings that claimed serious adverse drug events had more than doubled in an eight year period to 2005, many of which were new and unexpected. Meanwhile, Merck's Vioxx (rofecoxib) episode in 2004 and the recent Avandia (rosiglitazone) setback, where GlaxoSmithKline's diabetes blockbuster was found to increase the risk of heart problems, have left a shadow over the agency over its dealing of the incidents. According to the report, the FDA has taken steps to address the concerns noted in the past and agreed with four of the five recommendations laid out in the report - to develop a clinical trial database, create an institutional review board registry, create a cross-centre database tracking BiMo inspections, and to seek legal authority to provide oversight that reflects current clinical trial practices. The FDA did not address the recommendation to establish a mechanism to provide feedback to BiMo investigators on their inspection reports and findings. "FDA pointed out that BiMo inspections make up only one part of it's efforts to ensure human subject protections, noting that it views its protocol review before a clinical trial commences as the most important step in protecting human subject," the report said of the FDA's response to the document. In reply the office said in the report: "We note, however, that this report addresses another important part of the system for protecting human subjects: oversight of the trials once they are actually underway." In a statement released by the agency, the FDA said: "The report issued by the Department of Health and Human Services Office of Inspector General offers valuable insight into FDA's programme to protect clinical trial participants. The agency agrees with the report and is already acting on all its recommendations. Volunteers play a critical role in making treatments available that help millions of patients and FDA is committed to ensuring strong oversight to protect participants." Last week's reauthorisation of the Prescription Drug User Fee Act (PDUFA) is hoped to go some way in addressing the safety monitoring of drugs by increasing the powers of the FDA and providing an overhaul of the system. As part of the legislation, the FDA would have the powers to request post-approval studies, and manufacturers would have to post clinical trial results of approved products on a public database.
The report by the Office of Inspector General focussed exclusively on the FDA's onsite inspections through its Bioresearch Monitoring Programme (BiMo) where the FDA determines whether the sponsors, clinical investigators and institutional review boards responsible for the clinical trials comply with relevant regulations.