Cancer Clinical Trials Are In A ‘State Of Crisis’
20 CommentsBy Ed Silverman // April 16th, 2010 // 8:57 am
Not good news. And improved treatments will be delayed and patient lives will be lost unless the efficiency and effectiveness of the clinical trials system improves, according to a new report from the Institute of Medicine, which was commission by the National Cancer Institute to review its Clinical Trials Cooperative Group.
At issue are concerns the CTCG program can’t conduct timely, large-scale, innovative trials needed to improve patient care. The average time required to design, approve and activate a trial is two years, and only about half of all trials undertaken are completed. Meanwhile, funding since 2002 had dropped 20 percent, while knowledge about predictive biomarkers and molecular changes has grown.
To remedy the problem, the IOM says the CTCG needs to better respond to emerging scientific knowledge; involve broad cooperation of stakeholders; and leverage evolving technologies to provide high-quality research that can change practices. Four recommended goals:
- Improving speed and efficiency of the design, launch, and conduct of trials;
- Incorporate innovative science and trial design into cancer trials;
- Improving prioritization, selection, support, and completion of clinical trials;
- Provide incentives to patients and physicians to participate.
M. Black
How about instead of the dinosaur method and mixing a random blend of chemicals, we focus on new types of therapy. Enough has been proven in my experience.”
patrons99
Why not mandate the early-initiation of outcomes studies with hard clinical endpoints (all-cause morbidity, mortality, and survival), not surrogate endpoints and definitely not economic endpoints, as one of the absolute conditions for market approval?
patrons99
This comment is only partly tongue-in-cheek:
Why not use Advanced Market Commitments and the G8 to effectively use the Third World as “volunteer test subjects” for new cancer agents? Guinea pigs sounds a little too harsh a descriptor.
http://en.wikipedia.org/wiki/Advance_market_commitments
http://www.vaccineamc.org/about.html
http://www.vaccineamc.org/about.html
http://www.gatesfoundation.org/vaccines/Pages/advanced-market-commitments-vaccines.aspx
http://www.cgdev.org/section/initiatives/_active/ghprn/workinggroups/amc
patrons99
We all have compassion for patients with cancer. New cancer agents offer hope for patients with cancer. I strongly favor a compassionate use exception to the usual new drug approval process, which in some instances is a lengthy process. If granted such an exception, however, we could inadvertently cause greater morbidity, mortality, and shorter survival. Thus, to offset this uncertainty, outcomes studies should be initiated immediately as an absolute requirement for approval. As always, the informed consent is critical.
Former Pharma Marketing Director
Is it possible that industry and the NCI are competing for the same patient bases?
Major cancer centres should be mandated to complete some trials that are non industry sponsored.
We need to look into rare cancers and see what trials we can get underway in this under-serviced area. We need to look at trial design for rare cancers as well.
We need more involvement from independent patient groups. They could take on a bigger role of patient education which might improve patient accrual.
Greg Pawelski
Donald Berry, Ph.D., professor and chair of the Department of Biostatistics and Applied Mathematics at M.D. Anderson Cancer Center stated in the January 2006 issue of Nature Reviews Drug Discovery, the statistical method used nearly exclusively to design and monitor clinical trials today (the frequentist method) is so narrowly focused and rigorous in its requirements that it limits innovation and learning.
He advocates adopting the Bayesian methodology, a statistical approach that is more in line with how science works. It is used routinely in physics, geology and other sciences. And he has put the approach to the test at M.D. Anderson, where more than 100 cancer-related phase I and II clinical trials were being planned or carried out using the Bayesian approach.
http://cancerfocus.org/forum/showthread.php?t=3093
patrons99
Thanks Greg.
I have been using a rudimentary form of Bayesian methodology in my day-to-day outpatient internal medicine practice for quite some time now. I’m not a biostatistician. Briefly stated, I try to limit my test ordering to just patients who based on clinical grounds have at least moderate pre-test probability of having a particular disease in order to lessen the incidence of false positive test results.
Could you summarize for us how Dr Berry’s use of Bayesian methodology in cancer-related phase I and II clinical trials will be more efficient than the current system?
anon
This clinical trials thing seems to be intertwined with the FDA critical path initiative…. which is a critical path for industry to make money, with the help of the FDA. Industry members make up most of the critical path initiative board along with pro-industry FDA types.
The critical path are trying to adapt clinical trials to industries needs-make them quicker and less patient orientated.
The clinical trial industry know that oncology is the next money spinner. it must be on the top the list for the FDA Critical pathers or eschenbachers.
scary, scenario.
Greg Pawelski
patrons99
One example of the use of Bayesian methodology in cancer-related phase I and II clinical trials was the BATTLE program, a clinical trial design applying Bayesian adaptive randomization for targeted therapy development in lung cancer.
A $9 million U.S. Department of Defense research grant (hence the name BATTLE) to help clinicians develop biomarker-integrated approaches of targeted therapy of lung cancer elimination. It was a novel clinical trial program to explore and prescribe treatments based on the genetic and molecular profile of a patient’s tumor.
After a panel of tumor markers is identified and assessed, patients with advanced NSCLC are enrolled in one of several trials testing agents that target abnormalities in their cancer. A novel adaptive randomization statistical design was applied to the clinical trials to accelerate the identification of highly individualized treatments for each individual patient.
Investigators studied the mechanisms of response or resistance to existing and newer targeted agents, explored novel signaling pathways for future trials and identified molecular features in tumor and adjacent normal tissues that correlate with treatment outcome.
However, the importance of mechanistic work around targets as a starting point could have been downplayed in favor of a systems biology approach were compounds are first screened in cell-based assays, with mechanistic understanding of the target coming after validation of its impact on the biology of the cancer cells.
Many of these drugs cry out for validated clinical biomarkers to help set dosage and select patients likely to respond. Optimal and reproducible targeted testing continues to evade the diagnostics of the disease. Numerous genes, tumor, and patient factors contribute to the risk of the cancer coming back and the effectiveness of chemotherapy.
It could be vastly more beneficial to measure the net effect of all processes (systems) instead of just individual molecular targets. The cell is a system, an integrated, interacting network of genes, proteins, and other cellular constituents that produce functions. One needs to analyze the systems’ response to drug treatments, not just one or a few targets (pathways/mechanisms).
There are many pathways/mechanisms to the altered cellular (forest) function, hence all the different “trees” which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indivudal trees.
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=36349
http://clinicaltrials.gov/archive/NCT00409968/2007_01_19
Big Red Bruce
Don’t these findings suggest one more series of factors that will continue the push of clinical trails East? As if, cost savings incentives were not enough. Does the CTCG need a better scientific arm or better yet more scientific collaborators in the field to guide study design using more state of the art science/technology?
Michael Kirsch, M.D.
Many of the outcomes in cancer research I’ve read over the years have been clinically meaningless. Success is often defined by shrinking tumors or declining markers, when the only outcomes that matter to patients is if they live longer or better. Much of this literature is infested with surrogates, which are of no use to living breathing patients, even though the research is much easier to perform. http://www.MDWhistleblower.blogspot.com
Greg Pawelski
At the end of the day, the only clear conclusion possible after more than 20 years of these cooperative group trials of empiric chemotherapy in cancer is that there is no clear and meaningful advantage associated with any form of therapy ever examined in these trials.
Bernard Carroll
MARK TO MARKET MINDSET IN RESEARCH
@ Michael Kirsch:
Your comment about surrogate endpoints is on target. These were introduced by the Smartest Guys in the Room to replace real clinical endpoints when the research enterprise was failing to deliver the promised goods. I call this the academic version of mark to market accounting, for which Jeffrey Skilling at Enron is infamous. It calls for booking projected profits from a deal before actually making a profit. In medical research, this tactic serves the purpose of keeping the dollars flowing and keeping the game going.
Bernard Carroll.
Nancy
MARKET MINDSET CONTINUED
I have not finished reading the 295-page document, however I wanted to stop and comment on one of the committee’s findings….
“Although career development awards and mentorship activities are encouraging, the committee found that these actions do not appear to be resulting in robust improvements in ensuring a pipeline of well-trained, motivated investigators willing to make career commitments to clinical research [page 202].”
Why? I would venture to guess that the mentors were too busy “consulting” with the product manufacturers to properly supervise and train the new investigators.
And what is the career development money being spent on if not supervision and training?
The committee recommended that investigators receive training, mentoring, protected time, and recognition. Nothing new here. They just need to figure out who is going to “enforce” the recommendations.
likeitis
The report introduction (not many people read beyond there do they?) mentions incentives for investigators twice in one page.
The excellent comments on this thread show that throwing more money at the problem is NOT the first or last or easy or correct answer.
Lets see some closely reasoned justifications for action, guys; the usual academic whining for more money won’t wash; most observers are now aware of the wastefulness and personal (noble or Nobel?) biases built into the present systems…..
patrons99
@ Greg Pawelski (1:43 PM):
Just as a point of clarification, could you help me understand when and why the Department of Defense starting sponsoring cancer research studies? Real question.
http://online.wsj.com/article/SB10001424052748704508904575192051659802366.html?mod=WSJ_latestheadlines
http://newswise.com/articles/battle-trial-confirms-efficacy-of-personalized-medicine-in-lung-cancer
Greg Pawelski
patron
Good question!
http://www.defense.gov/Releases/Release.aspx?ReleaseID=780
http://www.conferencemedia.net/store/stores/aacr/american-association-for-cancer-research-annual-meeting-2009/department-of-defense-funding-opportunities-for-cancer-research.html
patrons99
Greg -
Thanks for the links to DoD and cancer research.
You are obviously current as to the latest direction and theories in cancer research. There was a time, quite some while ago, when I was doing basic research (organophosphorus, carbohydrates, nucleoside, and nucleotide chemistry) into cancer.
With the advent of genomics and plans to sequence the DNA of all tumors, I have a question for you, and it may have a very simple answer:
How certain are we that cancer is less a disease of gene mutation, than it is a disease of gene transfection between species? e.g. SV-40.
patrons99
Sorry, Greg. Let me rephrase the question. Rather than cancer being a disease of gene mutation, might cancer instead be a disease of gene transfection between species?
http://industry.bnet.com/pharma/10007729/everything-you-thought-you-knew-about-cancer-is-about-to-change/
Greg Pawelski
patron
Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways - network of genes - of tumor cells can be known in sufficient detail to control cancer. Each cancer cell can be different and the cancer cells that are present change and evolve with time.
All a mutation study can tell you is whether or not the cells are potentially susceptible to this mechanism of attack. It cannot tell you if one mutation-inhbitor is better or worse than some other drug which may target this. In different tumors, one or some other drug, might do better or worse than the other.
There is a tumor biology laboratory test that has accurately identified patients who would benefit from treatment with these molecularly-targeted therapies. The assay is able to test molecularly-targeted anti-cancer drug therapies like Iressa, Tarceva, Tykerb, Sutent, Nexavar and others, because of being small molecules. The test can discriminate between the activity of different targeted drugs and identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs.
Sometimes targeted drugs can be used, but they can never find the correct one for the “individual” patient by using molecular tests (they never even test the drug against the tumor cells). Most times, targeted drugs need to be used with conventional cytotoxic chemotherapy. Sometimes they can find a combination of targeted drugs that may work.
What is still not understood by purveyors of the Cancer Genome Project is that the original Human Genome Project dealth with a homogeneous population of normal diploid cells. This is different from primary tumors, which are heterogeneous and have a genomic signature unique to every patient.
When it comes to “predicting” the best treatment for the individual, unlocking the complexities of a person’s DNA is not the answer, it is simply a starting point. In fact, just recently, a March 16, 2010 study in the Journal of the National Cancer Institute looked at the value of various gene tests and concluded none of the studies showed a clear usefulness.
Genomic tests provide lots of information about a patient’s genes. However, there are so many sequences in our DNA which influence disease, attempting to unravel such complexity just produces more and more information without a particularly useful benefit. While genes may provide a recipe, they do not determine the end results and cannot predict how an individual will respond to a specific treatment.
Like the various influences on a flower seed that cause one blossom to turn out differently from another, there are biological processes in the body that affect the development of cancer in each patient and determine how that patient’s cancer cells will uniquely react to treatment.
Despite its allure, the “genetic” path is not all that personalized. Treatment based on genetic testing is still a guessing game (trial-and-error). But a treatment regimen based on a “functional profile” – a real-time test of chemotherapy on the actual cancer tissue – can predict with accuracy an individual’s response to chemotherapy.
Cell-based functional profiling measures the response of the whole cell to drug exposure, using a combination of morphologic and metabolic endpoints. It is measuring at the cell population level than at the single cell level. The morphologic endpoint information is gathered by examing the state of hundreds of individual cells. The metabolic endpoints measure the combined metabolism of all cells present in the culture. In theory, a gene expression assay analogous to what a cell-based profile does, would measure 100,000 genes before and after drug exposure. The sort of gene expression assays that are being done measures gene expression in the “resting” state, prior to drug exposure.
With regard to cancer recurrence, cell-based profiling tests do correlate very well with patient survival, by simply looking at the survival of the tumor cells in control cultures, along with the strength of their cell “robustness” in culture and patient survival. The more “robust” the tumor cells in culture, the shorter the patient survival.
Gene profiling tests, still important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for “individual” patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess.
It will never be as effective as the cell “function” method (is the cell being killed regardless of the mechanism), which exists today and is not hampered by the problems associated with gene expression tests (does the cell express a particular target that the drug is supposed to be attacking). That is because the cell-based profiling measures the net effect of all processes within the cancer, acting with and against each other in real time, and it tests “living” cells actually exposed to drugs and drug combinations of interest.