Project Zero Delay: Maybe There is Hope for the Clinical Trials Process After All!
Posted by Dr Pennell on August 26, 2009 - 3:16 pm

OK, I hope you all aren’t bored to tears by this topic by now, given two related posts in April and again earlier this month describing the “broken” clinical trials system and the challenges to performing clinical research in the current environment. However, I thought this would be a good follow up post to let all of you know that the laughably obstructionist policies in place that prevent timely processing of clinical trials are being recognized, and that something is being done to fix it.

Clinical trials designed to test new cancer therapies are the only way that potentially effective drugs can make if from research labs into cancer patients in dire need of help. In April I talked about a couple of recent papers (see link above) that documented the complicated process of opening a clinical trial, involving hundreds of distinct processes in the bureaucratic morass of review, and taking multiple years from submission to trial opening.

In an early release publication in the Journal of Clinical Oncology, a group led by Dr. Razelle Kurzrock at the M.D. Anderson Cancer Center in Houston describes a new streamlined process for getting a phase I trial approved and the first cancer patient enrolled in what must be a record time (aptly called “Project Zero Delay”). This paper begins with a very interesting review of the myriad problems with the current system. For example, the authors note an average of 4-5 years for a company to take a new drug from the lab through enough initial safety studies in animals to get to clinical trials. After that, there is another 7.5 years before a promising drug makes it to FDA approval! All of this while over half a million people per year are dying of cancer in the USA, and of course millions elsewhere. The group then describes many of the same details I mentioned in my initial post about the delays in getting a specific trial opened.

Project Zero Delay focuses just on this aspect of the problem, namely getting a single new trial open. MD Anderson took it upon itself to also look at the exorbitant delay in opening trials, and designed a plan to fix it. The first step MD Anderson took was to negotiate a master agreement with a particular pharmaceutical company that would cover all trials over a 3-5 period, designed to overcome the months of budget and contract negotiations that normally take place for a new trial.

Most of the remaining problems with this process can be related to sequential levels of bureaucracy. In other words, drug companies, academic institutions, and the federal government each have an enormous amount of steps necessary to produce what is known as an Investigational New Drug (IND) application and then to open the trial, and these operations are usually done sequentially (one after the other) rather than simultaneously to be efficient. Project Zero Delay was designed to have all regulatory processes happen in parallel rather than sequentially, so that when the final OK came from the FDA the trial could open immediately.

The protocol described in the paper was designed cooperatively with the company and the MD Anderson principle investigator (PI). As the PI of a number of trials myself, I can tell you that the way it normally works is I write a protocol and then send it back to the company for review. This can then start a back and forth review and re-review process that can literally take years. In this paper, the authors were able to streamline this by having the company and PI cooperate at the inception of the concept so that the protocol could be completed fast. Read the rest of this entry »

Challenges with Clinical Research
Posted by Dr West on August 3, 2009 - 11:28 pm

Thanks to GRACE member speedpuppy for highlighting the link to a New York Times article on the one of the key obstacles to meaningful progress in cancer management being the difficulty of getting clinical research completed.  It discusses challenges from both the patient and physician perspective.  Only about 3% of patients in the country enroll on clinical trials, and in lung cancer it’s lower than that.  Not suprisingly, clinical trial participation is heavily skewed toward academic centers, so many community practices participate in little or no clinical research.

There are certainly challenges from the physician perspective.  The leading one is that clinical research is generally a financially disadvantageous option for a physician and a practice.  Clinical trials tend to take much more time per patient than managing patients outside of clinical research.  They often provide the same or less money than the cost of running the trial for each patient.  They also require more attention to following the precise treatment plans of a protocol.  Larger research centers require extra nurses and administrative staff to oversee the details of clinical trials, and this is a significant investment.  And the paperwork involved is a royal pain, requiring time that many docs just don’t feel that they have.

From the patient perspective, some people are very wary of being a “human guinea pig” in clinical research (a mindset fostered by some media outlets trying to generate controversy), and in the US in particular, patients are often extremely wary about participating in clinical trials with a placebo for some patients, even though a placebo-controlled trial is often the best way to really learn how effective vs. toxic a new treatment is.  In truth, many of the most important trials in cancer are now done outside of the US, where more patients are willing to accept some uncertainty, and partly because the alternatives may be less favorable.   Importantly, trials may require considerable effort to find, and they often entail travel to participate, for unclear benefits.  Finally, it’s also important to note that many patients who want to participate in trials are unable to do so because they aren’t eligible, often due to prior treatments or other medical problems.  A recent study that did a chart review in the Kaiser system in California found that only 15-30% of patients there were eligible for various clinical trials in advanced NSCLC.

The idea for restricting eligibility is to provide a more homogenous population of patients with an anticipated similar prognosis.  However, trials often include restrictions that are unnecessarily limiting.  This can leave patients without options and slows the pace of our progress in the field.

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The Clinical Trials Process is Broken? Well, Duh!
Posted by Dr Pennell on April 11, 2009 - 10:41 pm

  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!

Clinical trial system

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