From the GRACE Archives - Originally Published April 11, 2009 | By Dr Pennell
This week in the Journal of Clinical Oncology, a group of clinical researchers and specialists in management science took it upon themselves to study and report, in depth, the processes that the National Cancer Institute (NCI) and its developmental clinical trials branch, the Cancer Therapy Evaluation Program (CTEP), use to design and approve new clinical trials for promising anti-cancer agents. There has been a general consensus for years that new clinical trials were taking way too long to move from concept to reality, and they wanted to look at the possible reasons behind it.
As you probably know, clinical trials are research studies that prospectively enroll patients with a particular disease state (for example, metastatic NSCLC) to an experimental treatment that is hoped to be better than the standard treatment. The most important trials are the phase III “randomized” trials, in which patients are randomly assigned to either the new treatment or the current standard treatment. This is done to balance out any random elements of the patients so that both groups are relatively evenly matched for things like age, sex, performance status, etc. This type of trial is what was used to bring drugs like Avastin (bevacizumab) into common use.
For example, say drug X shows great promise in an early phase trials, and I want to design a phase III trial to bring this great new drug to approval by the Food and Drug Administration (FDA). I write to CTEP with an idea to test this drug, in combination with, say, Tarceva (erlotinib) in a phase III trial compared to Tarceva alone in NSCLC patients. I send in the concept, and CTEP then initiates its review process to determine if this is something they want to fund.
Here is the general outline of the process. It begins with review of the concept, and if the concept is approved it moves to the protocol development group. Once the protocol is finished, it goes to an institutional review board (IRB; whose primary function is patient safety) as well as some other administrative reviews, before moving to activation.
Sounds straightforward, doesn’t it? Ha!
What the study group discovered was that for every step of this simple process, there were a dozen or more extra steps that needed to be passed, and if you failed any of them, you had to start all over again! Here is an illustration of the steps needed just to get the concept to a formal initial review (from the first blue box above to the second):
I know this is hard to read, but it illustrates the point: this is a ridiculously bloated and overly-cumbersome process. In fact, they found that there are 296 distinct processes required for new phase III trial activation: at least 239 working steps, 52 major decision points, 20 processing loops, and 11 stopping points.
The result? The average time from submitting a concept to enrolling the first patient was 602 days, or nearly 2 years! Some trials took 4-5 years to activate. This is actually better than a prior study of phase III trials activated through the Cancer and Leukemia Group B (CALGB; one of the large, NCI sponsored cooperative groups) in this decade, which required 370 distinct processes and took an average of 784 days!
While 160,000 lung cancer patients are dying each year in the United States alone, this is completely unacceptable. And it is not much better for small trials at individual institutions. It is not at all uncommon for a small phase II trial, designed by an unnamed intrepid clinical lung cancer researcher, to take a year or more from concept to opening of the trial. My own institution has 90+ processes involved in opening a trial, which I have to think is a bit excessive but seems relatively simple compared to what is shown above!
The study points out that there is no one particular step that is leading to the delay, making fixing this problem problematic. Part of the problem is the sheer number of people who have input into these trials. The IRB is a necessary protection for all new clinical trials, but why do there need to be so many regulatory steps? Certainly we could all take lessons from the pharmaceutical industry, which is able to get phase III trials up and running in a much shorter period of time when patent life and revenues are on the line!
In an accompanying editorial, David Steersma quotes John Godfrey Saxe: “Laws, like sausages, cease to inspire respect in proportion as we know how they are made”. I would hope that the recent spate of prominent papers exposing the ridiculously overcomplicated phase III trial initiation prcedures will somehow bring about reform and streamlining of the process. So far, it seems to be the problem everyone recognizes but no one is willing to tackle.
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