Defining Success in Clinical Trials: Is Learning Something Enough?

Posted by Judi Space on Thu,Jul 25, 2013 @ 06:00 PM

Avastin discussed at ASCOAt last month’s ASCO conference, rapt attention was given to a presentation on the clinical trial results for the drug Avastin for patients recently diagnosed with an aggressive form of brain cancer, glioblastoma multiforme (GBM), according to an article by Clinton Leaf appearing in the New York Times, which is summarized below, with our comments added. The presentation by Dr. Mark R. Gilbert, professor of neuro-oncology at the University of Texas M. D. Anderson Cancer Center, revealed earlier clinical trial results that were encouraging:  tumors shrank and the disease appeared to stall for months in two smaller single-arm studies.

No Difference

However, Dr. Gilbert’s larger double blind study of over 600 brain cancer patients found no difference in the survival rate for patients given a placebo with standard treatment vs. those given Avastin with standard treatment.  In effect, the larger, more reliable double blind study eliminated doubt as to the general effectiveness of the drug.   In other words, the trial was “a success” because it had a clear result, but we learned that the drug has no statistically significant impact on the disease as a whole. But is that enough for the trial to truly be deemed a success?

It depends on how you define success. On one hand, doctors have no additional information on how to successfully treat brain cancer as a result of the study. On the other, one possible solution has been eliminated, so doctors and pharmaceutical companies can continue their quest for an effective drug armed with the knowledge from the study.

Not so Fast

The problem is that it is not quite as cut and dried as all that. Some patients who take Avastin do significantly better than those who do not. However, the trial failed to reveal the responders that make this result possible. Despite 400 clinical trials over 16 years, no correlation has been made as to why Avastin works or fails to work in certain patients. Again, given that we don’t know, can we deem the trial a success?  

Individualized Factors May Hold the Key

Researchers are learning that individualized pathology and physiology may be significant factors in developing effective drugs for treating certain diseases.  The variability of tumors and cancers at the genetic level can be great, as can the way our genes affect our response to drugs. So the solution to some diseases may lie in identifying the drugs that best align with the individualized factors associated with a given disease.

Failure rates in clinical trials tend to increase significantly as the drug moves from phase I to phase II. In the final phase it is not unusual for trials to wholly contradict earlier trials, or for the benefits to be far less than what was first reported, according to a 2005 paper published in the Journal of the American Medical Association by Dr. Ioannidis, an authority on statistical analysis.

The Difficulty of Matching Clinical Trial Populations to Patients

Rules governing statistical trial enrollment typically produce trial populations of younger and healthier members than those likely to use the drug. In addition, trial populations typically have had far less medical treatment. These factors combine to form somewhat of a mismatch between the trial population and patients. Given that the vast majority of drugs that enter clinical testing fail to get approved (95%), finding ways to match clinical trial participants with the appropriate genetic or molecular signature may be paramount to finding drugs that work.  

That’s the approach taken by Genentech in developing Herceptin, a breast cancer drug that targets tumor cells with an abundance of the HER2 protein. Small clinical trials were designed that enrolled only those with the required molecular or genetic signature. 60% of the new drugs in development at Genentech/Roche are being developed in concert with a diagnostic test to determine patients most likely to benefit. They did not go that route when they developed Avastin and tested it in patients with GBM.

Back to the Question at Hand

So, is it enough to simply learn something from a clinical trial, even if we don’t find a solution to treat a disease? Given that there is so much riding on finding drugs that improve and extend the lives of those suffering, anything that moves us forward, even if only eliminating what was thought to be a potential solution, is a step in the right direction.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They have offices in the United States, United Kingdom, and Switzerland.

Tags: FDA, Oncology, Targeted Therapy, Cancer Drug Development, Oncology Clinical Trial Design, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Glioblastoma, ASCO

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