By Don Sharpe
As usual, the NCCN annual meeting held on March 9 – 13 in Hollywood, Florida, featured a timely and topical expert roundtable, this one titled “Molecular Testing – Implications for Practice and Policy”. The panel discussion featured Scott Gottlieb, MD, American Enterprise Institute; Louis Jacques, MD, Centers for Medicare and Medicaid Services; Michael Kolodziej, MD, Innovent Oncology; Mark Kris, MD, Memorial Sloan Kettering Cancer Center; Lee Newcomer, MD, MHA, UnitedHealth Group; Andrew C. von Eschenbach, MD, formerly of the NCI and FDA, currently with Samaritan Health Initiatives; and Elizabeth Thompson, Susan G. Komen for the Cure.
Moderated by Clifford Goodman, PhD, Senior Vice President, The Lewin Group, the expert panel assembled to discuss the regulation of molecular testing, and it would appear that there is strong consensus and agreement that there needs to be more order (and less chaos) around molecular tests.
Currently, it is not required to attain FDA approval to market and sell laboratory developed tests (LDTs) or what the panel referred to during the discussion as “molecular or genetic tests.” The expert panel was charged with debating whether the data gleaned from these tests is clinically relevant; and in light of the cost of the tests, to discuss if there is value in the tests, should the healthcare system pay for the tests, and should the tests be regulated by the government in the same way as drugs and biologics.
To begin the discussion, Dr. Goodman asked for clarification on the existing regulation regarding these tests. Dr. Gottlieb pointed out that current regulation is determined by three criteria:
To clarify further, if it is a high complexity test it must be performed in a high complexity lab such as a CLIA lab, whereas if the test is marketed as a test kit, it can be performed in a less complex lab such as those at a community hospital. Additionally, if it is a CLIA waived test, it can be performed more easily at the point of care such as a physician’s office.
What concerns the FDA, according to Dr. Gottlieb, is that molecular tests are regulated based on how they are marketed, not based on complexity or the claims being made about the test. If the test is marketed as a kit, it must be FDA approved, but if the test is being performed as a service inside a CLIA lab, it is regulated by CLIA and does not require FDA approval.
Dr. von Eschenbach, formerly of the FDA, clarified that the problem with the lack of governmental regulation today is that it leads to too much heterogeneity and variability of the tests. The variability that occurs in the tests makes it difficult to interpret any of the data from them. He said that standards and platforms need to be put in place “to reduce variability and make the information valuable. We’re laying a foundation here and it is important that we get it right because we have to build on it.”
Dr. Jacques, with his CMS perspective, first noted that CMS spends more money on healthcare than any other country. When asked to clarify what a “homebrew” is, Dr. Jacques said that a homebrew is a laboratory developed test which is essentially performed out of a single lab as opposed to being distributed in a kit. An example of a homebrew is the OncoTypeDX test from Genomic Health in California. Regarding payment for OncoTypeDx, the local Medicare carrier at the time, NHIC, was able to make a coverage determination within their jurisdiction (in California) and it ended up having a nationwide impact on policy coverage even though it wasn’t a national coverage determination.
Next up was Dr. Kolodziej, the practicing oncologist in the group, who framed the issue of accuracy/variability of molecular tests by stating that 10%-15% of NSCLC of a certain ilk are EGFR mutated. At the same time, he says he can’t remember the last time he saw a patient positive for EGFR mutation, and that makes him wonder if the test is any good. That seedling of doubt from the provider obviously puts doubt in the mind of the payers – federal and private – as to whether they should be paying for the test.
Dr. Newcomer informed the group that UnitedHealth spends $1.3 billion on chemotherapy and $4 billion on cancer care annually for the commercial population that they serve. Dr. Goodman asked, “If you’re spending that much money on cancer care, and you know these tests may not be accurate, how confident are you that you are spending those dollars efficiently?” Dr. Newcomer responded that he is not at all confident that molecular tests are improving the efficiency of United’s spending, and that he does not know how much United is spending on molecular tests or what they are getting for that spend.
When the panel was asked how to improve the certainty of the tests, Dr. von Eschenbach said that “it is obvious we need to bring order out of chaos.” He believes that the FDA is best prepared and best positioned to do that, at least from a scientific and analytical infrastructure. First, a decision needs to be made as to who’s in charge and then it will be necessary to bring the FDA up to a level of capacity and capability to create platforms and standards. CLIA can play a role in the transition to greater regulation, and then it will be necessary to put the issue in the hands of the agency best prepared to handle the science and regulation.
Dr. Kris of Memorial Sloan Kettering told the audience that when a new NSCLC patient comes in, the patient is given DNA-based tests which have been shown to predict whether a patient will respond to therapy. The two best examples of this are the tests for K-ras and EFGR mutations. At MSKCC, they do 8 genetic tests on incoming cancer patients. Tests are done in a multiplex system meaning individual tests can’t be ordered as the tests are all done automatically. Dr. Kris said that there are only about a half a dozen cancer centers that routinely do these tests.
The problem with this, Dr. Jacques said, is that CMS is then asked to pre-pay irrevocably for all of these tests, when in fact, it is still too early to determine clinical utility. “Although, the tests results, generally, have proven that they have meaningful clinical benefit.”
Dr. Newcomer was asked by Dr. Goodman whether United evaluates the clinical data or the health outcomes associated with these tests? What comprises real evidence? Dr. Newcomer said they look for three things:
Elizabeth Thompson, representing the patients in the debate, pointed out that this is a very challenging topic for patients. “In the US, we are leading the world with these tests, but we still don’t have enough information to make informed decisions. Even at leading cancer centers.” She feels as though educated patients are pretty informed about the problems with the tests, but there are many, many patients that place their trust in what their doctor tells them, and she is afraid that the doctor may not have the right information.
Adding a dose of reality to the discussion, Dr. Gottlieb pointed out that he thinks there will be a new regulatory scheme attached to molecular tests in the next 12 to 24 months. “The FDA is working on regulations, and if they don’t act unilaterally, then The Hill is working on legislation that will be attached to authorization of the Medical Device User Fee Act of 2013, which would change the regulatory scheme for all of these tests. The operative question for all of us is what is the risk that these tests are introducing? You have to ask that because you want the regulatory paradigm to be based on the risk, to regulate to the risk.”
Dr. Jacques brought the discussion back to the clinical evidence, “if you can give me good evidence of clinical utility, I’m going be very happy, and anything short of that will cast a pall of uncertainty over the test and will make me wonder if we should be paying for the test.”
Dr. Kolodziej was asked how well is the information from these tests understood and used? He said, that “when the test matters, we do it. I have to be pragmatic. Meaning, I don’t have the specimen so first I have to convince the hospital to send the specimen to a commercial laboratory, then I’ve got to convince the payer to pay for the test, and then I’ve got to interpret the results.”
Moving on to value for money, Dr. Kris told the audience that the EGFR test is roughly $800, while other more commonplace tests are pretty much free. Dr. Kolodziej iterated that “we don’t know whether there is value for the money yet,” and echoed that this is still an immature system. But he is cautiously optimistic that there will prove to be value in some molecular testing, and “it will prove to be predictive of a response to therapy.”
Regarding value for money, Dr. von Eschenbach also said that there is no question that these tests are a methodology for saving money and costs in healthcare. “These tests are intended to reduce the variance around the mean, and when you reduce variance around the mean, quality, by definition, goes up. Patients will be getting the right treatment, the right dose, for the right reason, and in the end will get the right outcome. And what goes away in this process is waste.”
Also commenting on value for money, Dr. Newcomer said one of the problems is that the system needs a new billing process. Currently at United, they can determine when they’ve been billed for tests but can’t decipher what tests were performed. The coding system is very antiquated.
Dr. Jacques stated that as a matter of policy, CMS doesn’t evaluate cost effectiveness. Bottom line on this topic, he said, “is that everything about cancer is expensive. Genetic or molecular testing may be expensive, but so is chemotherapy, hospitalizations, and serious adverse events.”
Thus, it would appear that the panel of experts was in agreement that molecular tests are in an early stage of development, that these tests have the potential to deliver great value if they prevent unnecessary therapies or conversely allow important treatments to be delivered, and hopefully improve quality while reducing healthcare costs. It also appears that this group would welcome regulation in the next 12 to 24 months as a way to build a platform which will improve accuracy of the tests, and deliver better clinical utility.
It appears that there was a critical point missing from the debate. Innovation was touched on, but probably not adequately represented in the roundtable. Where was the molecular test manufacturer during the debate? LDT manufacturers would argue that by incorporating more regulation, the innovation which could lead to greater value will be stifled. Everybody on the panel is aware of this argument, but didn’t seem concerned about it. Neither did the audience, as the question did not come up during the Q & A session.
The problem is that these tests are not priced like a therapeutic. A course of Avastin at $50,000 delivers more revenue/profit to the manufacturer than a molecular test manufacturer could hope to attain. Without the margins available to them, the regulatory and risk hurdles that molecular test manufacturers face may be more than they can fund. It doesn’t seem fair to apply the same regulatory hurdles to molecular test manufacturers that are applied to prescription drug manufacturers. And if we do, will we see the innovation slowly deteriorate because of the hurdles.
The debate regarding regulation of molecular tests will go on, but as Dr. Gottlieb points out it seems pretty certain that greater regulation is coming. The hope is that that greater regulation will improve accuracy, payment, and outcomes.
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