Editor's Note: For the past half century, the cooperative clinical trials groups funded by the National Cancer Institute (NCI) have played an integral role in advancing the field of clinical cancer research. The Institute of Medicine (IOM) was tasked by the NCI with assessing the state of cancer clinical trials, reviewing the cooperative group program, and providing advice on improvements. Their report is now forming the basis of a series of changes being implemented at the NCI and in the cooperative groups to ensure that the system maximizes efficacy and efficiency in the coming years. In an interview with Medscape, Robert L. Comis, MD, Group Chair of the Eastern Cooperative Oncology Group (ECOG), an NCI cooperative group member, discusses some of the key issues raised in the IOM report and looks at how changes in cooperative group structure and funding might affect the future of clinical cancer research.
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| Robert L. Comis, MD |
Medscape: Let's start with some background on clinical cancer research. What are the primary sources of funding for clinical cancer research?
Robert L. Comis, MD: There are 3 major sources of funding: the pharmaceutical industry, the government and, increasingly, not-for-profit foundations. But the 2 principle funding mechanisms are still the government and industry.
Roughly $150 million per year is allocated by the NCI to the cooperative groups to conduct clinical trials. These funds are expected to cover costs for all trials -- trials in kids and in adults, phase 2 and phase 3 trials, large randomized trials and smaller, less extensive trials. At the same time, however, a pharmaceutical company can pay $150 million for just 1 study. The level of funding is an order of magnitude different.
Medscape: If a physician is thinking about enrolling a patient in a clinical trial, what benefit would he or she have to enrolling in a trial that's run by a cooperative group?
Dr. Comis: In general, a few things might attract participating physicians to the group system. The trials sponsored by the cooperative groups tend to ask more scientifically generated questions rather than simply comparing drug A vs drug B. There is a broader portfolio of trials across the groups that include rarer tumors, for example. There is direct involvement of both academic and community doctors in the group system. Community doctors get to participate in the design of the studies and the execution of the trials, so the trials tend to focus on questions that are important to their practices, a bit beyond what might be asked by a pharmaceutical company.
Medscape: Is there a downside?
Dr. Comis: Yes, 1 downside is that the level of reimbursement for the research costs that are involved with placing one's patients into clinical trials is much lower than the actual cost for government-funded trials. It is important to point out that the cost for routine patient care, which is generally defined as care that would be covered for nonclinical trial costs, such as x-rays, laboratory work, office visits and the like, is generally covered by insurance. But research costs would likely include additional lab work or scans for the patient, and the data management and regulatory compliance that is required for the physician and their staff. The government reimburses the research costs at about $2000 per patient case, but we estimated several years ago that it cost a median of about $6000 per case. This places a burden upon cancer centers, hospitals, and other institutions that participate in cooperative group studies to make up the difference; the physicians who are dedicated to putting their patients on trials end up donating their time and effort, and that of their staff, to do so. This lack of reimbursement is a key challenge nowadays considering the rising cost of medicine, in general.
Remember, physicians are not required to participate in medical research as part of their license to practice medicine. Their involvement in clinical research is completely voluntary to begin with, and then the need to donate their time, and also encourage cost-sharing on the part of their institution to participate in government-funded studies, creates a tremendous reliance for us on loyalty and volunteerism. There is a danger in being so reliant upon cost-sharing and volunteerism in the current healthcare environment wherephysicians and institutions are facing decreasing fiscal margins, which have been used in the past to support this effort.
Medscape: Aside from the financial disincentives, what are the other key drivers preventing physicians from participating, and what is preventing patients from enrolling in trials?
Dr. Comis: With regard to the patients, we've conducted 2 large national surveys and identified some fundamental issues. One is that awareness of clinical trials as a treatment opportunity is quite low at the time of their diagnosis and before treatment decisions are made -- in the range of 10%-15%. So the vast majority of patients are never really aware that they might be able to participate in a clinical trial for their cancer treatment.
With regard to physicians, it takes additional time to get the patient in the study rather than simply giving them conventional treatment. Between additional staff time, additional physician time, and less reimbursement, there are both financial and practical forces working against enrollment.
There is considerable regulatory oversight associated with putting a patient in a trial. We carefully execute these studies and scrutinize how they're done on the practice level. So doctors who participate in clinical trials by the government or even by the pharmaceutical industry have to be willing to have people come in and actually audit their records. Thankfully, there is a cadre of physicians who are voluntarily committed and willing to do this, but we are also aware that this might be a disincentive for others.
Medscape: One of the issues raised in the IOM report was the flattening of research funding over the years. What effect do you see this having on clinical cancer research moving forward?
Dr. Comis: If you go back to the late 1990s, there was a substantial infusion that occurred at around the time of the doubling of the National Institues of Health (NIH) budget, which raised cooperative group funding from about $90 or so million to $160 million. It peaked in 2002 or 2003 and, since then, it's either been flat or decreasing.
As the IOM report presented, the cooperative group system is important for the patients and the country, and it should be supported at higher levels of federal funding. The cooperative groups are advocating for this as well, so that we can maintain a robust portfolio of trials that is large enough in number to have options available for patients across the many disease types and stages. Continued flattening in funding may lead to fewer trial opportunities for patients, which is a bit disconcerting to think about since we've always encouraged patients to participate in studies. The NCI currently has a budget of around $5 billion. Within the current national spending constraints, in general, I think everyone is very concerned that the NIH and NCI will experience cutbacks, along with many other federal agencies. In this environment, the only other option left to support increased funding for clinical research is some reallocation of NCI's existing budget.
Efficiency is also important. We realize that the current clinical trials system needs to become more efficient, and there has been a lot of emphasis and attention placed on this recently, with some success.
Medscape: If NCI were to reallocate funds, what would you see as the best way to use those additional funds to help the cooperative groups move cancer research forward?
Dr. Comis: There must be an increase in the research-related case reimbursement level to bring it in line with the actual costs to do the work. Beyond that, I would like to see us enhance the system and make it more attractive to do cutting edge studies that focus on the use of biomarkers and various techniques to identify selected groups of patients who are most likely to benefit from the new approach. The cooperative groups have the capacity to do this now. ECOG just coordinated TAILORx or PAACT-1, the largest study in breast cancer ever conducted that was driven by cancer gene-based markers. It enrolled 10,000 women, and we evaluated their genetic markers and designed their treatment plan depending on those markers. ECOG's trial in stage II colon cancer (E5202) looked at 2 molecular markers before assigning the patient to a study arm.
Trials are becoming more complex and expensive. As we continue to use molecular markers and design trials based upon what happens to those markers, there will have to be additional resources committed to doing the laboratory work and/or the imaging work required to answer the scientific question. We have to integrate biomarker laboratories and imaging programs into our normal workflow. We'll need to have core laboratory and imaging functionality built into the structure so that we can tap into it.
Another key piece would be a group-wide information technology system. The government is going to have to provide the common technology structure that works with our current systems.
The same is true for tissue acquisition and procurement. Across the groups, there are several large tissue banks that have the best clinically annotated specimens available. We see the need for the government to support harmonization of information technology around our banks, so that we can broaden access by more researchers across the country and throughout the world.
Medscape: What about regulations within and outside of the United States?
Dr. Comis: We have to address the tremendous regulatory burden associated with running clinical trials -- we estimate that $0.35 of every dollar goes toward the regulatory burden in some way.We're regulated by the NCI, by the US Food and Drug Administration (FDA), by the Office of Human Research Protect (OHRP). Although Centers for Medicare & Medicaid Services isn't directly involved, their regulations affect us because the clinical care costs of our elderly patients have to be coordinated with them.
This regulatory burden also affects our position as the research engine for the world. In general, the majority of patients who are on phase 3 pharmaceutical studies are outside of the United States because of the regulatory burden that we have in this country. It's easier for us to tack on to a study in Europe than it is for the Europeans to work with us, partly because OHRP guidelines require that their patient safety laws be virtually the same as ours. It doesn't make a lot of sense that we can't work with countries like Germany and France in a very easy way.
As we learned working with the epidermal growth factor receptor inhibitors, there are clearly genetic differences in different ethnicities. With the development of smaller subsets of disease based on various molecular and genetic characteristics, we need international cooperation. So, somehow our government will have to loosen up a little bit and make it easier for us to cooperate with our international colleagues.
Medscape: How optimistic are you about the future of the cooperative group system and clinical cancer research?
Dr. Comis: I am very optimistic. The IOM report made it clear that everything has to change, not just the groups but all stakeholders. The NCI has to change, the NIH has to change, the OHRP has to change, and the FDA has to change. We're all committed to change and are willing to change, but it has to be all for the better and it has to be fast. We're already having discussions with the NCI, and the discussions to date have been positive It's just the beginning. There's much more work still to look forward to.