Are international clinical trials regulated? By the FDA? By anyone?

In gentle language, the U.S. Department of Human Services says that one of its own fiefdoms, the FDA, has been unable to keep up with the rapid growth in clinical research outside America. The push to find clinical trial patients outside the U.S. is not news. But the HHS review of FDA is still sobering: the agency is clearly struggling to monitor research overseas.

Understood in a political context, the HHS report is not intended as a research project or an investigation (despite its origins in the Inspector General's office at HHS). Rather, the objective seems to be to protect the FDA from budget cuts—or even to start to make the case for new programs or regulations. d9A2t49mkex

Such hypothetical programs or regulations could be more tailored to a research landscape that has been international for some time. But any changes appear to be a distant prospect, as none of the mild language of the report includes any new requirements or deadlines for regulators, sites or sponsors. Indeed, given that they are writing about risks to human patients in poor countries, the HHS examiners sound strangely neutral and friendly, almost as if scolding an aged family dog.

That tone may not resonate outside the U.S., especially if a corporation running a clinical trial in some distant country should misbehave. The fictional treatment of such an event exists already in book and cinematic form: John le Carré's The Constant Gardener.

Foreign Growth

For its 33-page document, the HHS reviewed data from 193 complete trials, both of drugs and biologics, associated with products approved by the FDA during 2008. Roughly 8 percent of the marketing applications reviewed by HHS had exclusively foreign data. An impressive 87 percent of the patients enrolled in the biologic approvals were located overseas.

International sites had far greater luck in finding patients. During 2008, they enlisted an average 550 subjects per site versus just 75 in the U.S. (The HHS watchdogs duly noted that a single large trial in Sweden skewed those numbers, but we suspect there might be a similarly large trial in any time period.) Overall, some 80 percent of the applications for the new drugs and biologics included data from non-U.S. patients. In absolute terms, more than half of all sites and patients during the 2008 period were international.

The rate at which the FDA traveled to inspect foreign sites (0.7 percent of the time) was less than half the inspection rate for U.S. sites (1.9 percent). The HHS compiled a table of countries that the FDA never visited in 2008, along with the number of patients recruited in those nations. The top seven countries on the list were all in Latin America: Peru, Colombia, Chile, Panama, Venezuela, Nicaragua and the Dominican Republic.

For some reason, FDA employees seem more inclined to visit safe, familiar countries in western Europe. Is it a coincidence that industry is pushing trials into less-inspected nations? Will there be a new rush at FDA to inspect everything in Latin America?

Five-Day Limit

As a matter of policy, it turns out, FDA inspectors can only spend a few days at each site. For site personnel abroad, that bit of information could help investigators stall an inspection and run out the clock.

As the HHS report noted: "Inspectors are generally allowed 1 week, including travel time, to conduct these inspections. FDA is unable to easily extend the inspections if significant compliance issues or other problems arise." The cost of each foreign FDA inspection is pegged at an eye-popping $40,000; but the methodology of computing that cost is not included.

The report notes that the FDA is exploring an automated way to select which sites will be inspected on the basis of "risk." But the HHS offers no other details about how risk will be calculated. And the FDA is wholly unaware of many international trials which are not being run under the IND filing requirements.

Finally, sponsors are failing to submit fully completed IND or BLA packages, with plenty of missing data about patients. The HHS said that leads to additional blind spots about the safety of those patients. Those projects may be submitted to the agency at a later date, or may always remain off its radar screen.

Targeting Paper

The report is intriguing in that the HHS may be channeling the concerns of the academic community and of some of the FDA's own technical staff. The HHS report had five sources of data: 1) approved FDA marketing applications and corresponding review documents; 2) FDA inspection documents; 3) clinical investigator data from investigational new drug (IND) applications; 4) interviews with FDA reviewers in each of 18 divisions at the agency; and 5) FDA policies, procedures and guidance documents.

Surprisingly, the report does have a clear verdict on one minor villain—paper. Data for eight trials were submitted on paper and entirely lost in the bowels of FDA warehouses. Another 21 studies had partial clinical trial datasets. Said the HHS: "The sponsors failed to provide site locations and subject enrollment in the clinical study reports, and in other cases, appendixes that were supposed to contain the information were missing."

As a remedy, the HHS is recommending "standardized electronic clinical trial data," but declined to venture into the fraught territory of which standards (CDISC's or those of HL7), much less whether paper would be lightly discouraged or just banned.

The HHS also recommends a single "internal database" for clinical trial data at FDA. But that recommendation is sufficiently vague that it will probably be easily sidetracked inside the agency or incorporated into a peripheral IT project. Borrowing language from the business world, the HHS also invokes "quality," but more as a buzzword than a transformative concept.

FDA Statement

In a folk-song spirit of interagency cooperation, the FDA was permitted to comment on the HHS report in an appendix. After plowing through the usual pleasantries, the reader comes to a few substantive passages that the FDA attributed to deputy FDA commissioner Joshua Sharfstein, a former Congressional aide and the agency's #2 official.

Sharfstein outlines what the agency is already doing to work with regulatory counterparts outside the U.S. That conforms to one of the HHS's noncontroversial suggestions, which is for the FDA to work with foreign regulatory bodies. He also notes that U.S. law prevents the FDA from forcing sponsors to file INDs for trials outside the U.S., in effect creating a legal limbo zone for many trials that the HHS report doesn't thoroughly examine. One short-term idea is to tweak the rules to allow a variety of trial registries, from and the World Health Organization, to track such projects.

But Sharfstein also points out that there may be other obstacles to more foreign inspections. "FDA's efforts to ensure data integrity and safety and protection of human subjects must be respectful of the sovereignty of other countries," he notes. Oh, and one other thing. "Resource constraints limit the number of foreign clinical trial site inspections that can be conducted...Inspections are usually conducted after a clinical trial is completed, too late to fix any problems."

U.S. Decline

The ramifications of the report may have more impact than its nebulous conclusions. The rising prominence of international research sites foreshadows a marginalized, downsized role for U.S. scientists working for industry. With a few percent of them abandoning pharmaceutical projects every year, American clinicians are simply not finding the needed numbers of patients in the U.S. And a global industry has naturally located a crucial component elsewhere.

If the present trends continue, U.S. investigators will be added to industry projects for ceremonial and marketing reasons, not for contributions to a trial's statistical power. The torch has been passed. The Peruvians will do the heavy lifting.

Down the road, the HHS report could become a gotcha document in the event that a global clinical trial unravels. At that juncture, the usual anti-industry experts can be expected to pontificate; the FDA will point to its earlier pleas for more money. In an instant, an outburst of anti-American media coverage could disrupt the currently favorable patient-recruitment dynamics outside the U.S., just as Bhopal and Coca-Cola turned people in India against multinational firms.

For an industry that is increasingly reliant on outsourcing, one morsel of good news in the report is that contract research organizations (CROs) appear to have escaped the scrutiny of HHS. That doesn't mean the CROs won't be singled out in some new report. It just signals that the HHS, in its deliberate way, was able to identify more glaring weaknesses at FDA at the moment.

Here's a link to the PDF version of the HHS report #OEI-01-08-00510 on FDA oversight of international clinical trials.