New and evolving strategies for clinical trial design are under way, a point that was made abundantly clear April 25th at the NCCN Policy Summit on Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies.
Ramaswamy Govindan, MD
New and evolving strategies for clinical trial design are under way, a point that was made abundantly clear April 25th at the NCCN Policy Summit on Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies.1Points without clear consensus at the summit, however, involved diagnostic biomarker testing: what tests should be used, when and why these assays should be administered, and most importantly, who will pay for them.“We have mutations, alterations, and overexpression. Next-generation sequencing looks at the whole thing. Complete analysis is an easier way to find patients. It is a way of identifying patients,” said panelist Ramaswamy Govindan, MD, director of thoracic oncology, codirector of medical oncology, and professor of medicine at the Washington University School of Medicine. Govindan believes in conducting a comprehensive panel on each patient upon diagnosis.
Fellow panelist David Flockhart, MD, PhD, director of the Indiana Institute for Personalized Medicine and chief of the Division of Clinical Pharmacology at the Indiana University School of medicine, focuses much of his research on pharmacogenomics. Flockhart also feels that collection of the sample should be the first step for every patient to determine if the patient may be treated with currently approved therapies or if he or she is appropriate for enrollment in a clinical trial. However, he feels that too many tests may not provide useful answers. “The questions are: if you do the broad testing, is that, in aggregate, valuable; is the broad testing useful; and if we do single tests, what are we missing?”
Currently, only 3% of cancer patients participate in clinical trials,2and one way to identify subsets of patients appropriate for clinical trials of targeted therapies may be large-scale biomarker panels or next-generation sequencing. Alan Venook, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center, agrees with many members of the NCCN panel that the enrollment of patients in clinical trials, which study targeted therapies, needs to increase. “We need to broaden the reach of clinical trials. Patients with a rare disease can go on the Internet and find each other, but we cannot find subsets [of patients] that are very specific,” Venook said.
Amy McKee, MD, lead medical officer at the US Food and Drug Administration (FDA), believes that comprehensive panels overall provide a more elegant and efficient clinical trial design process, and she stated that the FDA is open to using sequencing and different platforms in clinical trials “If we know what it [the biomarker] is, then we can design better trials, potentially with fewer patients, because we know how the patient may react.”Whether the test is a single-gene assay or next-generation sequencing, administered upon diagnosis or upon metastases, and whether it be administered for the purpose of trials or treatment, all these issues become mute without the money to pay for the testing.
“The very first human genome sequencing cost 1 to 3 billion dollars,” said Govindan “Now we do whole genome [sequencing] for a few thousand dollars. Payers should be open to largescale testing, because it is similar to the cost of single-gene sequencing,” he said.
Al Benson, MD, FACP, professor of medicine at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, agrees that if insurance routinely paid for biopsies, it would bring much more efficiency into the system. “If we don’t do it, it will be harder and harder to identify subsets over time.”
However, according to Jennifer Malin MD, PhD, medical director for Oncology for Care Management at WellPoint Inc, the cost of full screening for every cancer patient would be enormous. She stated that her company’s foundation supports research, but she thinks that asking the payer to partner is a much different question than asking companies like hers to pay for a full panel of testing when the results may not be actionable.
Rosemarie Hakim, PhD, is a senior research advisor in the coverage and analysis group of the Center for Clinical Standards and Quality of the Centers for Medicare & Medicaid Services. “The reason we don’t outright cover everything is that we want to look at whether or not the treatment benefited the patient.” She referred to Section 1862a1A of the Social Security Act, which states that no payment may be made for any expenses incurred for items or services, which “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”3
“We have to look at evidence regarding why the FDA approved the test. Then we would do our own literature review. If there is enough evidence, then we would cover, but if not, we might cover it in certain research situations,” Hakim said.
Govindan expressed frustration regarding reimbursement circumstances, such as when a patient wants to enroll in an appropriate clinical trial and the third-party payer refuses to pay, so the patient cannot afford to go on the clinical trial. Govindan thinks that increased coverage of more genetic tests may prevent patients from being administered ineffective therapies, “which can result in higher costs for the payer in the long run,” he said.
“We are in this pickle because of our own brilliance,” Govindan said. “Cancer is a very complex genomic disease. We have the tools to learn the data. How do we get from current science to changing laws and paying for it?” Benson agreed that the science is way ahead of the structure in place to interpret the value of this information. “It is an evolving structure,” Benson said.
Flockhart pointed out that the value to the health care system as a whole needs to be considered, even though it may mean higher costs at the front end. “Think about the ultimate cost of therapy and disease, including costs avoided,” he said.
Govindan believes that reimbursement needs to look ahead for information on future decision making. “We are worried about the thunder storm, and there is a tsunami headed in our direction,” he said. “Cancer care is being transformed from acute care to chronic care. The cost is going to cripple this society,” he said.
The panel agreed that it may take more than a 1-day summit to answer these complex questions, and it will also take a wide scope of institutional players from the private and the public sectorspayers, pharmaceutical companies, diagnostic institutions, academia, the FDA, the NCI, the NCCN, advocacy groups, research and education firms, IT companies, and so forth—an effort that moderator Clifford Goodman, PhD, of the Lewin Group called an “interesting dance” of collaboration. Michael Deininger, MD, PhD, said he is “morbidly optimistic” that the answers regarding biomarker testing will come. “Optimistic, because there is some value in it for everyone,” he said. “The question is, can we get people to see it. Morbidly optimistic, because cancer is complex,” Deininger said. “This is not the end of the story.”