Finding Answers in Clinical Research
The Cancer Center's new Associate Director talks about the challenges and opportunities in bedside research.
As Associate Director, he has direct responsibility for advancement of research involving patients with cancer. He is also responsible for enhancing the Cancer Center's clinical research infrastructure, including the Office of Clinical Research, the Clinical Cancer Research Committee, and the Safety and Data Management Committee. It's a huge and critical job, but one that Dr. Ernstoff, who is a member of the Hematology Oncology Program, approaches with the thorough and articulate thoughtfulness that is his hallmark. A few months into his new post, he sat down with Focus to discuss clinical research at the Cancer Center.
Focus: Tell us about your new responsibilities as Associate Director for Clinical Research.
Marc Ernstoff, MD: One of the goals of the Cancer Center is to enhance and develop the understanding of human cancer and, by understanding human cancer better, to enhance strategies for prevention, diagnosis, and treatment. To be successful you need to study human disease in humans and that's clinical research. As the Associate Director for Clinical Research, my role is to help generate an environment that is conducive to human investigation of cancer—to assure that the portfolio of clinical research that is ongoing at the Cancer Center is robust, that the infrastructure needed to support that research is present and functioning, that the research is being conducted in an ethical and high-quality fashion, and that the research is moving from data to manuscript to publication.
The financial environment has become much more difficult for obtaining grants and federal funding. As Associate Director for Clinical Research, how do you plan to help researchers deal with this challenge?
The Norris Cotton Cancer Center is an NCI-designated cancer center with a significant portfolio of innovative and relevant research being conducted by highly skilled basic and clinical scientists. As an NCI cancer center, we have an already established infrastructure to develop, review, and conduct clinical research. This infrastructure includes a scientific review committee, a safety committee, and a clinical research office to oversee the collection and management of data as well as the regulatory components related to human investigation. We also have laboratory shared services that allow us to investigate hypothesis-driven biologic and correlative endpoints, as well as a biostatistical service, which provides support for design and analysis of trials, and a bioinformatics shared service that helps to evaluate potential correlative endpoints in a robust way. This already established infrastructure facilitates clinical research here, providing us a significant edge in writing grant applications.
But the current financial environment for supporting research is challenging, particularly for clinical research. Clinical research uses clinical trials as the method of investigation, and these trials may take three to four years to complete, with additional years to allow maturity of the data to a point of publication. The timeline for laboratory research is much shorter, where you might work on a new experiment every six months. Another challenge in the grant area is that clinical research with embedded laboratory correlative endpoints is very pricey. What you can perform for $200,000 in a laboratory is just a fraction of what you can buy in developing a trial for patients. Another benefit of being a NCI designated comprehensive cancer center (CCC) is that there are CCC-specific grants, which narrows the denominator when applying for funding.
Why does clinical research require such a huge commitment of time?
There are basically three components to answer that question. The first component is the time it takes in writing the trial and obtaining not just the financial support to conduct the research, but getting the study through the various regulatory agencies involved. For example, a clinical trial involving a homegrown vaccine, of which we have a number here at the Cancer Center, requires an FDA-approved investigational new drug license, and that requires an application of probably many hundreds of pages of documentation. It's not uncommon for these applications to take two or three years to finalize and get through the FDA. Once the study is approved by the FDA and other regulatory committees, the second component is accrual of subjects. The investigators have to identify eligible patients willing to undergo an experimental therapy and care for them during their participation. If the conclusion of the trial is survival, the investigators have to follow subjects over a long period of time to document their outcome. Finally, you have to analyze the data and prepare a manuscript, which can take up to a year. When you look from beginning to end, it can take many, many years.
Given that kind of time commitment, coupled with the challenging financial environment for funding clinical research, are you finding that young physicians are more reluctant now to go into clinical research?
It is a remarkable time to be a physician involved with cancer care. There are breakthroughs in understanding the causes of cancer, understanding the nuances of individual cancers, and in opportunities for new therapeutic agents—it is truly an explosion, volcanic in its pace. The knowledge is expanding, and with every turn of the page there's a new therapeutic hypothesis, there's a new therapeutic agent that is available. So I think there's a huge amount of excitement for young physicians.
But there are many challenges for young physicians interested in clinical research. First is commitment of time. Second is energy. Third is knowledge, coupled with imagination and ingenuity. Finally, the young investigator has to be able to find the resources to conduct research, particularly investigator-initiated research. To successfully compete for both internal and external resources to support clinical research, the clinical investigator has to generate some preliminary data to justify their approach and be able to articulate his/her proposal in a succinct way—one has to basically sell their concept and plan to his/her colleagues, that their idea is better than anyone else's.
On the other hand, there are other opportunities for young investigators to participate in clinical research through the cooperative group systems or networks. These mechanisms allow us to make available new agents and therapies in the context of communities of scientists. We've just been selected to be a member of the Cancer Immunotherapy Trial Network, an organization of about 20 major immune therapy-oriented centers around the country that will band together to try to move new immunological therapies in an effective and rapid way. There are many opportunities in cancer research that allow young investigators to be involved. I think there's a lot of excitement.
Are there any areas of clinical research that particularly excite you right now?
There are a many exciting areas in cancer prevention. With a growing understanding of the heterogeneity of causes of cancer, environmental and genetic etiologies and new understanding of the role of infectious disease in initiating cancer, we can develop novel strategies for prevention. In the area of diagnostics, new technologies are being worked out that allow for more sensitive and specific kinds of tests that might help people.
Dartmouth is very much involved with new strategies for diagnosing early breast cancer. We are exploring new techniques to perform higher quality surgery, with greater clarity defining the margins, using fluorescence imaging and other kinds of imaging intra-operatively. More limited surgical approaches can provide better outcomes with less morbidity. The new technologies will change the way people are treated.
Our knowledge is exploding in terms of understanding the pathways of cancer cell growth and pathways of repair that cells go through. This understanding has led to the development of new agents that influence those pathways and have lower toxicity profiles and will provide tremendous benefit. Understanding the complexities of human response to cancer, understanding the pathways of regulation of the immune system, and now having the tools to manipulate these responses is very exciting.
But embedded in the new technologies are challenges. For example, the recent observation that using spiral CT scans for early diagnosis of lung cancer brings up many more questions, and a series of challenges, as we begin to adopt this approach to the public and the greater society.
We are discovering that cancers are individual, that one kind of cancer is not exactly the same from one patient to the next even though they may have the same diagnosis. How do we address the conflict between developing truly individualized medicine with the need to standardize care to hold down costs?
The goal of personalized medicine is to fit the right treatment to the patient and not use treatments that are ineffective. Women with an evaluation of breast cancer back in the '70s and '80s were told that the cancer either expressed an estrogen receptor or it didn't. If it had an estrogen receptor, they were likely treated with an anti-estrogen as a therapy, and if it didn't they got chemotherapy. We now have much more knowledge about the different kinds of breast cancer, so the treatment is now focused on giving the patient the drugs and the treatment that are going to work best for their specific situation. This directed approach can save the cost of broadly treating everybody with the same treatment.
Obviously there's a cost in the development of a very specific drug therapy or treatment, but I think that in the global sense this is the start-up price of understanding cancer better. The ultimate benefit is that patients are going to get better treatments, and from society's point of view we're going to limit the cost because we're not going to treat all patients in a similar fashion, thus treating many with approaches that don't work. Personalized medicine will, a) improve outcomes while, b) decreasing the total costs of that disease to society. We are still challenged with the pricing of new agents and treatments. Health care reform will need to help us manage the cost effectively as we go forward.
September 19, 2011
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