As the industry scrambles to find the patients it needs outside the U.S., the organizers of the 2010 annual Drug Information Association (DIA) in Washington, D.C. decided to assemble the sort of luminary-packed panel discussions that only the DIA can present.
The session on multi-regional trials began with Doug Peddicord, executive director of the Association of Clinical Research Organizations (ACRO), and was followed by two high-level speakers from FDA.
Peddicord was able to review a now-familiar litany of data from clinicalrials.gov, the FDA-NIH repository. Peddicord estimated the decline in the numbers of U.S. projects at 5.5 percent annually, Europe’s drop at 6.1 percent. The winners? India, with growth in projects of 45 percent; and Korea, with a 27 percent increase. “If real estate is about location, location, location, clinical research is about numbers, numbers, numbers,” Peddicord said.
ACRO is in the process of trying to study whether there is any demonstrably lower level of quality to global studies. The early data suggest there is a comparable level of quality in most regions of the world. To prove that, the CRO group has collected data on 22 trials with more than 60 thousand patients. “There are not significant differences,” he said, although the research has not been completed or published yet.
One of the DIA panelists, the FDA’s Robert Temple, is no stranger to the DIA annual gathering. The FDA’s deputy director of clinical science at the Center for Drug Evaluation and Research (CDER), Temple somehow managed to say more in a few minutes of unscripted remarks than some speakers would be able to cram into a 3-day PowerPoint presentation.
Some academics have been concerned that a drug tested in, say, Brazilian patients might have different effects than in the more ethnically diverse U.S.
Temple was respectful of that perspective, but he clearly thinks that the response rates found in most countries around the world will generally converge. Referring obliquely to U.S. immigration history and the plethora of types of bundles of genetic material who found their way to the U.S., he implied that his working premise is that a drug that works (or doesn’t) in India will have more or less the same profile in Indiana. He implied the agency as a whole was coming around to share that view. In brief, he has no big problem with international research.
“It is hard for us to imagine why the direction of the response would differ,” Temple said of testing the same drug in different nations. Of suppositions about different responses to medicines in particular countries, he said: “The stuff is always called ‘ethnic.’ Nobody quite knows what that means. Are a lot of these things documented?”
Temple clearly views the increasingly international nature of clinical trials as a reality, and one that his FDA colleagues are fairly comfortable with. “We are seeing more and more trials that are multiregional," Temple said. "Which does allow you to compare. I think that’s attractive.”
His colleague Robert O’Neill, director of the office of biostatistics at CDER, is clearly on a different page. No less authoritative, but more severe in manner, O’Neill sounded more concerned, both about what industry is doing in so many countries around the globe—and about how effectively the regulators are watching that activity.
That set up a strange cognitive gap. Someone in the audience who only heard Temple’s remarks would leave the DIA meeting calm and relaxed. Someone who heard only O’Neill’s remarks would be girding for significant new regulation. Someone who heard both men might be a bit perplexed.
“There have been no improvements in study design that I’m aware of,” O’Neill said, noting the earlier concept of "bridging" studies has evolved into "multiregional" projects. But O'Neill seems to lament the inability to know whether 25 percent or 50 percent or 100 percent of the data from a trial in Shanghai, China are relevant to the population of northern Europe.
Given the quantities of data in multiregional studies, O’Neill said, society and regulators have some blind spots that make him nervous, especially about contract research organizations (CRO). “Who’s doing these studies in 2010? Where are all the investigators coming from? Who trains them?" O'Neill said. "We have no idea what’s going on. We don’t know the CROs in the game. That’s a piece that is not now dealt with. We’re going to have to close the loop on that.”
O’Neill is clearly concerned about the lack of a clearly defined role for the CRO industry under U.S. law or international good clinical practices (GCP) guidelines that guide most of what industry does. At the risk of stating the obvious, the U.S. academic community, wincing from losing its once-central role in biomedical research, has similar substantive concerns about CROs that cannot be dissociated from its own competitive predicament with the CROs.
O’Neill has no dog in that fight. But he sounds uneasy at the formally unregulated nature of international projects. He said regulators need visibility not just into the final statistical results of a trial, but into how those numbers were compiled. Under the present legal landscape, it's as if regulators need to analyze a new recipe without being told the ingredients or meeting the cook.
There was a forward-looking, futuristic tilt to some of O'Neill's remarks. “We’re talking about a new age where we would be asking for the whole package,” he said. “Why these sites? Tell me why you decided on 100 sites. Tell me about the Saturday morning training of your investigators. It seems to fall under the radar screen.”
O’Neill went on to say: “The problem with a modern clinical trial is you have a lot of hands in the game and a lot of subcontracting going on. The data is coming in in a lot of ways. This is the operation of the modern clinical trial. The problem is when the sponsor outsources their brains to the CRO and says, ‘It’s your baby. You do it.’ ”
Sponsors might never admit that they outsourced their brains. But the recent layoffs in the industry come close to requiring that, simply because there are not enough warm bodies left to run all the trials that Wall Street is assuming in its projections and spreadsheets.
The existing rules and practices at the regulatory level, O’Neill suggested, have not kept pace with what is actually happening in clinical development around the globe in 2010. “The CRO is the modern inferface to carrying the trial out,” he said. “The modern clinical trial is not written up that way [in legislation]. What went on behind the scenes to get the result is hidden from everybody, and that is a mistake.”
The proximity of any change to the existing regulations was impossible to gauge at the DIA gathering. O'Neill may merely have been expressing his own personal view, or the view of a small circle of people at the agency. Or its possible he was firing an early warning shot of some sort, presaging new guidance document or regulation that would no doubt take years to announce, revise and put into practice.d9A2t49mkex