Flaws in clinical trials show need for closer regulatory ties

A recent report by the US Department of Health and Human Services has nailed the US Food and Drug Administration (US FDA) for its role in monitoring and inspection of clinical trials done outside that country.

The report brings out very interesting data, which point out the flaws in the way clinical trials are approved. It illustrates how in 2008 the sponsors or pharmaceutical companies relied heavily on data from foreign clinical trials to support their marketing applications for drugs and biologics in the US.

As much as 80% of the approved marketing applications for drugs and biologics contained data from clinical trials, the report revealed.

The study went on to say that more than half of the clinical trial subjects and sites were located outside the US. This trend is only expected to grow, it indicated.

In that backdrop, the department highlighted that the FDA inspected less than 1% of the trial sites for applications approved in 2008 and went one step ahead in disclosing that the “FDA may be unaware of some ongoing, early phase clinical trials outside the US without the Investigational New Drug Applications.

As part of its findings, the department noted that in 2008, the FDA approved 129 marketing applications containing clinical trial data: 114 for drugs and 15 for biologics.

Of these, 121 applications contained sufficient information to determine whether sponsors submitted foreign or domestic clinical trial data: 106 for drugs and all 15 for biologics. It said further, “FDA was unable to locate the other eight marketing applications.”

More strikingly, 80% of approved marketing applications for drugs and biologics contained data from foreign clinical trials. In all, sponsors submitted 91 marketing applications for drugs containing at least one foreign clinical trial site or as much as 86% of the total approved drugs. Nine of these applications had exclusively foreign data, inferring that no data at all was generated from trials in the US.

The department conceded, however, that logistical challenges and submission of clinical trial data by the sponsors in a non-standard format hindered the FDA’s ability to monitor foreign clinical trials.

According to the report, one of the issues faced by the FDA inspectors is the extension in the travel and inspection time beyond the one week period prescribed under the rules. The note says the FDA is unable to easily extend the inspections if significant compliance issues or other problems arise.

Officials have reported to the department officials that work visas and translators are other obstacles to conducting foreign inspections.

On the costs, too, there seems to be some financial strain. The report quoted an FDA official who said that as sponsors conduct multi-site trials at increasingly more sites, fewer subjects are enrolled at any one site. With inspections costing about $40,000 each and the additional logistical challenges of conducting inspections at foreign sites, it may be more difficult for the FDA to justify a foreign inspection.

Clinical trials are becoming a subject of intense global debate as the nature of the business includes testing unapproved compounds on humans. Based on the safety profile and the comparative efficacy, the product is brought into the market.

The ease of available patient population for speedy completion of trials and the large savings on costs have made India a favourite destination of multinational companies but going by the concerns raised by the US health department on the FDA’s inability to keep a tight control on the trials, there appears to be a crying need to simultaneously review the Indian regulatory system in its entirety.

It is appalling that the FDA was unable to account for all clinical trial information because application files went “missing” or the sponsors failed to provide site locations and subject enrolment in the clinical study reports.

As part of its recommendations, the health department has suggested that the FDA should seek standardised electronic clinical trial data from sponsors and create an internal database. This will enable effective analysis of the data. It has also encouraged the FDA to closely monitor foreign trial and if needed take steps to encourage sponsors to file the Investigational New Drug Applications.

As an important step to regulate foreign sites in a better way, the health department cited the agreement between the regulatory body and the European Medicines Agency and recommended that the FDA should continue to develop inspectional agreements with foreign regulatory bodies.

The FDA does have an agreement to cooperate on various functional aspects with the Drug Controller General of India —- the Indian drug regulatory agency.

The loopholes discovered by the US health department should push the FDA to seek closer ties with the Indian authorities.

Clinical trials in India have zoomed from a few million dollars at the start of the decade to over a billion dollars now. As the number of clinical trials have multiplied, it may have been difficult for the Indian inspectors as well to keep a close watch on the trial proceedings to the desired level. Therefore, the Indian regulator will need not just additional training in handling trials, but also put far more resources at the right places.

Pillman is an executive closely linked to the global pharma industry.