Wednesday, April 2, 2008

Trials and Tribulations

It may be apparent from my most recent postings that, in my opinion, cooperative oncology groups around the world rarely use the inductive reasoning process. In the midst of a molecular revolution the main instrument for translating research findings from the laboratory to the clinic is, therefore not functioning as efficiently as it should be. When designed properly clinical trials can address fundamental questions. The design of a good therapeutic experiment should be driven by knowledge of the biology and natural history of the disease. For example, if you want to design studies to treat Hodgkin's disease, you need to learn to think like a Reed-Sternberg cell.
I envisage a group of cancer cells sitting in a corner laughing hysterically at some of our approaches to experimental design. Surgeons only willing to study the operation they were trained to do; medical oncologists always giving chemotherapy on days 1 and 8 because that’s when we have clinics; radiation oncologists giving treatments only 5 days a week because it is difficult to work at weekends. Often none of the above are willing to even participate in a trial unless they are assured of being part of the outcome. Cancer cells don’t think that way.

When involved in oncology therapeutic research you should always have in mind the five most important questions that can be addressed in clinical trials relevant to the oncology field. It is also important to know and be able to use the most appropriate human model system to address these questions. Of course there are no clinical cooperative groups organized to do this but there should be. Most groups specialize in studying a particular disease, or a particular stage of a disease. They should always have in mind the five most important questions that can be addressed in a clinical trial in that disease, or that stage of the disease. And, the questions should not be limited to questions facing a particular specialty.
How do you discern the most important questions of the day? Any individual or group responsible for a substantial clinical trials program ought to periodically participate in state of the art exercises, where experts are asked to define the major questions. And, these experts should not be limited to one’s own group. The end result would be questions that will apply to anyone anywhere studying the disease in question. Each group would then be unique only in the resources it can bring to bear on addressing a question. If we did this, there would be fewer individual group and more intergroup studies.
The larger the group involved the less the tendency there is to go through this kind of exercise. Groups become attached to their own specialties or their own studies. The focus is not on the best way to address important therapeutic questions but the best way to prove their approach is superior to someone else’s.
And, there is a tendency to do studies that address less important questions so that a clinical trial is available for each disease or stage of a disease that falls within the purview of a group. This is useful as a measure of the activity of a group when we review each other’s grants. So while we have a myriad of regulatory agencies and committees enforcing burdensome regulations ostensibly to protect patients, we spend precious little effort assuring that a clinical trial is really addressing a fundamental question. If you want to really protect the interests of cancer patients, for every trial you are asked to review, ask yourself where is the hypothesis? And, will the proposed study test it or try to confirm it?