1. There's an additional reason to be cautious in considering a clinical trial offered by a doctor: the possibility that the doctor has a conscious or subconscious stake in increasing the number of patients in a trial that may bias his advice or subtly influence the doctor to downgrade the potential of a standard or different therapy.

I don't think many doctors would give biased advice if the matter were clear cut, but for some of us with cases in the gray area, the doctor may have a readiness to believe that the trial would be reasonable for the patient coupled with a readiness to believe that other options do not offer an advantage. This is not an accusation; I think much of such bias occurs simply because physician researchers are human beings who have a special interest in advancing knowledge for the good of humanity. On the other hand, doctors are often paid up to several thousand dollars for enrolling patients in clinical trials, as I understand it; while that may often be a reasonable and needed incentive to attract the doctor's attention and cover his time to learn about and involve himself in trial administration, for some doctors financial gain is no doubt the key motivation. I can't see myself asking a doctor if he is being paid to offer me a trial; that would be unbelievably awkward. But maybe there is some other way to find out. Perhaps, if a drug is involved, calling the manufacturer and asking about enrollment fee payments to doctors would work. Does anyone have a suggestion here?

My own story is a case in point. Diagnosed with a dangerous case of prostate cancer (initial PSA 113.6, Gleason 7 (4+3)with perineural involvement and all cores positive, most 100%, stage 3 per DRE), several different doctors I consulted offered a clinical trial along with other options. I had an impression that large institutions that are involved in many trials may feel a subtle pull towards getting patients in those trials. One leading researcher discouraged patient empowerment as he wanted to be calling the shots and seemed not to be fond of patients in his trials wandering off the reservation by employing alternative approaches (such as nutritional practices).

I was told that some trials that I might qualify for had response rates as good as 40% in making the PSA fall by at least 50% for a while. In contrast to those odds, I found an
investigational therapy that appeared to have a very high percentage of patients, close to 100%, achieving a PSA "nadir" (PSA low point)not only 50% lower than at the
start but in fact close to zero using an ultrasensitive PSA test. This approach had been submitted for a clinical trial, but no company would support it with funding. The only evidence was from a couple of on-going clinical series. I was able to drop my PSA from 113.6 to less than 0.01. I was able to keep my PSA below 0.05 for more than a year, then make a decision after a total of thirty months on hormonal blockade to start the
off-therapy period of intermittent therapy. I was able to use a maintenance program (Proscar, Fosamax for my case, nutrition, exercise, and stress reduction) and stay off the heavy duty drugs (Lupron and Casodex) for thirty four months, though I had a boost from thalidomide for the last six months. The therapy was (and is) intermittent triple hormonal blockade. That response was far better than a 40% chance of a fairly temporary partial remission! (I'm now in my thirteenth month of a second cycle of triple hormonal blockade and confidently expect again to go off full therapy.)

I do think it is very important for us to enroll in clinical trials when it is reasonable in our
circumstances. I'm just saying that we need to be actively involved in determining whether a particular trial is reasonable for us, and we need to be aware of physician researcher biases.

Jim

Posted at 8:19PM on Aug 6th 2006 by Jim

2. The FDA is trying to develop better approaches to the design of clinical trials that can be adapted based on new and improved scientific information, that helps guide them to more effective use of medicines.

At present, clinical trials are highly empirical, they test drugs on general populations and then look for a clincial response and a treatment effect that is not likely to be a chance result. However, the side effect of this is inflexibility, which can limit innovation in the design and analysis of clinical trials. Some patients may unnecessarily be exposed to inferior experimental therapies.

Traditionally, researchers/drug developers would define cancer anatomically, and treatment choice would be determined by how each patient's tumor reacts to anticancer drugs based on that anatomical origin.. A new drug would be tested on everyone with a specific anatomical tumor type (lung cancer, breast cancer, ovarian cancer).

Then they would look for overall response rates that tie or beat (sometimes barely) existing therapy, hopfully without creating many new side effects (i.e. a new lung cancer drug may be deemed safe and effective if it shrinks tumors in 20% of patients). The example illustrates that doctors are given little information about which 20% of lung cancer patients are going to respond. And they found that anatomical-type tumors didn't correlate to how the cancers interacted with standard anticancer drugs.

The drug effect is independent of where the tumor came from in the body. Under current treatment selection methods virtually no chemotherapeutic drug has been successful in more than 50 percent of patients with advanced cancer. But instead of considering a drug that works only ten percent of the time a failure, it would be better to consider such a drug effective for one in ten tumors and to search for the agents among the current arsenal of chemotherapeutic drugs that will work for the rest.

Another problem with the empirical approach is it yields information about how large populations are likely to respond to a treatment. Doctors don't treat populations, they treat individual patients. Because of this, doctors give treatments knowing full well that only a certain percentage of patients will receive a benefit from any given medicine. They need information about the characteristics that predict which patients are more likely to respond well. The empirical approach doesn't tell doctors how to personalize their care to individual patients.

Having a good tumor-drug match not only would improve survival rates, it would be cost-effective, and the high cost of the newer cancer therapies reinforces the necessity of choosing the right therapy the first time around.

Posted at 9:22PM on Aug 6th 2006 by Gregory D. Pawelski