The outsiders: Unique team hopes to re-engineer the clinical trial process
Goal is to make CR faster, more efficient
One of the paradoxes of life is that it sometimes takes an outsider to help us understand ourselves.
Now there is a team of clinical trial outsiders whose research findings sometimes defy conventional wisdom, but just might produce answers the clinical research (CR) industry needs to survive and thrive.
A professor of management has teamed with a philosopher, a systems engineer, and an oncologist to radically redesign the way medical research is conducted in order to improve the efficiency of conducting clinical trials and save the industry billions of dollars and years of delays in getting new treatments to market.
"We have an interdisciplinary team and can apply management, engineering, philosophy, and medical principles to provide a multi-prong attack on problems," says David M. Dilts, PhD, MBA, co-director of the center for management research in health care (CMRHc.org), director of clinical research for the Knight Cancer Institute, and professor of health care management at the Oregon Health and Science University in Portland, OR.
While everyone agrees that it takes too long to get new therapeutics to market, they disagree on what causes these long delays, and few believe the system can be fixed.
"People think the system is what it is and there's nothing they can do about it," Dilts says. "One of our roles is to show what can happen and what has happened in other industries."
Some of the same barriers to efficiency experienced in health care research can also be found in projects conducted by the U.S. Department of Defense, says Steven K. Cheng, PhD, a senior research associate in cMRHc at the Knight Cancer Institute.
Cheng worked on large defense projects for the U.S. Navy and observed the way people would become bogged down in tweaking and continually "improving" systems, even when it was obvious if you stepped back that these minor adjustments produced no benefits.
"We were working on military projects where they'd spend countless months deciding on the color of lettering, when in fact it really didn't matter," Cheng says. "We find a lot of those things in common with medical research."
Ethical costs assessed
The cost of medical research delays can be quantified and documented. But few people discuss the ethical costs of such delays, which is an area of interest to Joshua S. Crites, PhD, also a senior research associate in cMRHc at the Knight Cancer Institute.
"Ethical scrutiny has been primarily aimed at clinical research once patients have begun to enroll," Crites says.
"We want to do more than provide stewardship of resources prior to their enrollment," he explains. "We want to find out what ethical issues exist prior to patient enrollment."
It's simple to drive home the point that we can do more from an efficiency standpoint and to note that new drug development time is excessive, Crites notes.
"But people tend to listen with a different ear when you say, 'You have a moral responsibility to reduce development time, as well,'" he adds. "Engage people in their wallets and also in their conscience, and that two-pronged approach is more effective in getting people to take notice and to implement or look for ways to solve some of the problems."
The team of Dilts, Cheng, and Crites, along with their colleague Alan Sandler, MD, has already published a number of studies that deflate the conventional wisdom among investigators that the "IRB did it."
Far from being the big time vacuum that many CR investigators believe, the IRB does not have the significant impact on research delays that people think, their studies have shown.1-3
For instance, one study found that the IRB review time and approval was the fastest process when compared with the scientific review committee review time and approval.1
The real culprit lays in synchronizing all the various pieces and people required to open a clinical trial, Dilts says.
"For example, it's been universal in every place we study that a major rate-limiting factor is contracting and grants, not the IRB," Dilts adds.
"Principal investigators are very aware of the IRB because they have to do something for an IRB submission," he explains. "With grants and contracts, they send in their information, and it gets done when it gets done."
But there are major issues that occur during the contracts and grants process that delay trials, Dilts says.
Some CR people couldn't relate to these findings.
"When I presented our study, people said, 'How do we solve the IRB problem?'" Dilts recalls. "I told them it wasn't the IRB and that if we did a dramatic decrease in the IRB time to review studies, it wouldn't make that much difference in the time it takes to open a study."
So people just asked Dilts again what they could do to reduce the IRB review time.
Research sites need to change the way things are ordered because a major barrier to faster and more efficient medical research is synchronicity, Dilts notes.
"If you have a scientific review committee that meets on the fifth of the month, and the IRB meets on the fourth of the month, then in most systems you have to wait an entire month for the IRB review," he explains. "One of the most dramatic ways to reduce study time is to make sure the meetings are in a synchronized manner."
So in the above example, an institution would schedule the scientific review meeting for the first of the month and the IRB meeting for the 7th day. This way investigators would have enough time to answer the scientific review board's questions. And the scientific review board would have enough time to approve the study before the IRB meets, Dilts suggests.
This cuts three weeks out of the review process without changing anything except for the order in which meetings are held, he says.
"The process to hold clinical trials is fraught with those kinds of issues," Dilts adds.
Delays predict problems
Cheng's research has found that when it takes a long time to open a clinical trial and enroll subjects, it diminishes the likelihood the trial will achieve its accrual goal.
This means that when investigators develop their CT faster, they are improving its ultimate likelihood of success, Cheng explains.
"We saw in oncology research that when studies take a long time to develop, the interest in those studies decreases, and now the studies are competing against other studies for patients," he says.
Another explanation is that perhaps studies that take a very long time to enroll patients are studies that are poorly-designed and perhaps should be stopped, but the system doesn't provide an efficient means for killing ongoing trials, Cheng says.
"A review committee might say, 'We don't agree with this study — please revise and resubmit it,' and studies tend to loop countless times until they finally get through the review process," Cheng says. "That's a waste of administrative and research nurses' time when you're working on a study that eventually will not accrue patients."
Yet this is precisely what happens often in the clinical trial industry, where nearly a third of CT sites never accrue any patients, Dilts notes.
Also, the clinical research industry does not weed out its low performers by moving contracts to the higher performers as happens routinely in other industries.
If a site doesn't perform well, it may not matter if the investigator is someone the pharmaceutical company values a relationship with, Dilts notes.
"The interesting thing is their success doesn't matter much," he says. "The pharmaceutical industry has created a novel thing called 'key opinion leader,' and once you're a key opinion leader, you can open a trial at your site almost regardless of your past success."
The novel team of Dilts, Cheng, Crites, and Sandler has recently moved from Vanderbilt University in Nashville, TN, to Oregon Health and Science University, where they hope to change the CR process at this institution and create a model that other research sites might emulate.
"Right now, we're taking on one institution, and if we can show it can work at this one institution, then we fully expect everyone to say, 'Wow! Let's go make some changes,'" Dilts says. "Everyone is gun-shy, and it's rare to make changes to major parts of a system, so we'll test the new system here."
References
- Dilts DM, Sandler AB. Invisible barriers to clinical trials: the impact of structural, infrastructural, and procedural barriers to opening oncology clinical trials. J Clin Oncol. 2006;24(28):4545-4552.
- Dilts DM, Sandler A, Cheng S, et al. Development of clinical trials in a cooperative group setting: the Eastern Cooperative Oncology Group. Clin Cancer Res. 2008;14(11):3427-3433.
- Dilts DM, Sandler AB, Cheng SK, et al. Steps and time to process clinical trials at the Cancer Therapy Evaluation Program. J Clin Oncol. 2009;27(11):1761-1766.
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