The cost of doing clinical trials is measured in time and expense, and all too often, futility, but recent changes may lead to more favorable verdicts in drug development.
 click to enlarge Study progression of a representative simulated trial demonstrating performance of rolling six over that of the 3+3 design. Data plotted as number of study patients vs. total elapsed time of trial in days. (Source: Jeffery Skolnik, MD) |
Two simple, one-word questions confront clinical trial managers: “Where?” and “How?” The answers are not as simple.
Where?
“There’s a growing crisis in the health care system of the West with the declining participation by investigators,” says Lawrence Meinert, MD, MPH, senior vice president of Medical and Scientific Affairs, Covance, Princeton, N.J. In his 15 years at this global CRO, Meinert has witnessed the falling off. “In days of yore, investigators worked 80-plus hours a week, but now you’re getting a generational effect. Clinicians aren’t willing to kill themselves like they did in the past.” The most experienced investigators, says Meinert, are disproportionately white-haired individuals who, when they retire, have no younger colleague of equivalent dedication to replace them. The financial incentive has also dropped off the map. “If you look over the last 15 years, pharma companies have treated investigators like a commodity, as if they were capitated HMOs—they paid on a procedure basis.” Unfortunately, over time, annualized increases in pay did not compensate for the actual rates of inflation.
How?
The big shift here, says Meinert, is that early clinical studies, Phase 1/1a, are being retained in-house at big pharma. “Proof-of-concept, dose selection … pharma is holding these very close in hand because that data is informing rapid-fire decision-making,” he says. Urgency and angst are the orders of the day. Fueling this temperament is the huge increase in the number of molecules chasing the same target; for example, non- small-cell lung cancer. “There are hundreds of these programs,” says Meinert. “And with the advances in technology, the capitalization effort to create an agent against that target has dropped.” So, the competition is fierce.
To reiterate: Where (not here) and How (right now). What is the solution of the “where” question?
Go East Young Man
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In a recent study published by Kalorama Information, New York, analyst Melissa Elder found that the off-shore clinical trial is no longer an exotic mirage, but a vital and growing component of drug development. For talent, consider India: “They have Western -trained, English-speaking doctors and professionals,” reports Elder. So the talent level remains constant while costs are down. Even more compelling is the availability of patients at a time when it’s increasingly difficult to recruit in the US. In India, willing patients are plentiful. “Most patients are treatment-naïve, and it’s diverse as far as their medical conditions—just a good mix of what some of these companies are looking for,” Elder says. Enrollment is rapid, and the resulting data may be more robust because of unusually high compliance rates. Says Elder, “Clinical trials offer health care at no cost in regions where it’s a necessity to be involved in any type of health care that can be provided.” So, whereas the dropout rate in a US trial might approach 50%, in foreign trials, it can be as low as 10%.
Off-shoring is not routine as yet, and difficulties remain. Intellectual property (IP) can be an issue in some countries (i.e., China); there are language barriers, regulatory dissimilarities, and ethical matters to consider. “There is a lot of controversy in places such as Mexico,” says Elder, “concern that companies will come in, treat patients, get the results and then pull out.” This leaves patients without the benefit of a drug they’ve helped develop. Regulations are now taking shape in a number of countries to prevent just that, as the off-shoring trend takes hold.
And Now the How
The aforementioned Phase 1/1a trials that have been sequestered in-house may be increasingly described as having an adaptive design. “‘Adaptive design’ is that which defines, up front, before we start the trial, how data that can be accrued in real time, and how can it be used within that trial in a pre-specified way,” states Michael Krams, MD, head of the adaptive design initiative, Wyeth Pharmaceuticals, adding, “What it is not, is an excuse for poor planning—doing one protocol amendment after another.” Adaptive design (AD) represents part of a change in the way Wyeth does business. It started with a seminal paper by LB Sheiner, “Learning versus confirming in clinical drug development” (Clin Pharmacol Ther. 1997). “Wyeth took this paper and made a business model out of it, so we now have Learn teams that are specifically set up to optimally explore early drug development,” says Krams. Facilitated by AD trials, these teams (theoretically) will accelerate go, no-go development decisions.
But how does that work in a blinded trial? “The data monitoring committee are asked to overlook the algorithm that is governing the decision-making process within an adaptive trial—to check if it all makes sense. So, yes, there is an ongoing look at un-blinded data to this fire-walled committee of experts,” Krams explains. The challenge is to ensure the integrity of the trial. As Krams puts it, “The information has to be considered as a sacred thing.” The really tricky part is how to manage this process so that the real-time learning is taken advantage of, but doesn’t result in an un-blinding by proxy. “Everything is set up so that these changes can occur as you go, but no change is visible to investigators, no change is visible to patients,” says Krams. And so the proof remains in the pudding. Wyeth has completed six trials, thus far, using this new AD method, and while the data is as yet proprietary, Krams is certain the cost savings have been, “in the millions.”
About the Author
Neil Canavan is a freelance journalist of science and medicine based in New York.
This article was published in Drug Discovery & Development magazine: Vol. 11, No. 3, March, 2008, pp. 34-35.
Filed Under: Drug Discovery
