Safety of CLL Treatment and Reimbursement

John L. Fox, MD, MHA: As an insurer, as a health plan, when we’re doing drug evaluations, we’re certainly always looking at a combination of multiple factors: safety, efficacy, and cost. When new drugs come to the market, how do we evaluate efficacy? Well, its best shown in the clinical trials data. How do we incorporate safety into that algorithm, into that calculus? Safety is, from our vantage point, really a concern of the provider and the patient to weigh the pros and cons, and the risks and benefits, of the toxicity versus the therapeutic outcome. I would say the only time that we really get concerned about safety is when we’re trying to choose a preferred agent and require one agent before another. If there is a black box warning or serious safety issues, we would never put that drug in front of another that didn’t have those same safety issues.

In fact, Zydelig was shown to have increased toxicity and increased death rates in treatment of first line CLL, in induction therapy in CLL, and isn’t recommended. So, I don’t think I have to tell physicians not to use that in that setting. But, the point is, I could never require a drug that had serious toxicities in front of one that didn’t.

At the end of the day, what everybody would like to know, whether they be a payer, patient, or provider, is what the optimal therapy is for anybody’s condition given their age, their comorbidities, their molecular markers, etc. The reality is that we don’t have that data, and we never will, in head-to-head clinical trials. There are no incentives and no requirements to do those types of trials, so we will have to rely on real-world evidence in order to generate that information about what optimal therapy is. The challenge with real world trials is you oftentimes don’t have all the information you need to make a decision or make inferences about what optimal therapy is. But, nevertheless, given the extraordinary cost-based therapies and some of the associated toxicities, we’re obligated to try and understand what that real world evidence shows.

There are a number of companies out there who are working on that today—Flatiron Health, as an example—that will try and generate that long-term data to look at the relative safety and efficacy. The reality is today, though, that physicians are deciding that, based on their experience with the therapies. They’re doing N1 experiments, and if they have a bad experience with a drug, that reduces the likelihood that they’ll use it in the future. That’s not good science, but its practical experience in how we use individual drugs. From the health plan perspective, though, given the mandates that we have to cover oncology drugs, the only way we could stand in the way of a physician using a drug would be to have a conversation with him or her about what the optimal therapy might be based on real-world evidence. Physicians are at risk for the total cost of care, and I think that’s an increasing trend. At least we’re studying that in this 5-year oncology care model. Physicians will be increasingly interested in that, as well, since most of these patients are on Medicare and most of them will remain in that practice until their deaths.

Today, when a health plan makes a coverage decision and a formulary position determination, it’s almost always based on clinical trials data. In the future, if we had real world evidence, would that change formulary positioning? Certainly it could, if there was compelling evidence and if it changed how the NCCN evaluated the evidence and its positioning. With all the drugs that are in the pipeline, though, by the time we get real-world evidence, it may be that that drug is no longer considered the standard of care. So, it’s a real challenge, not only in generating that data, but understanding whether or not it will even be relevant by the time we get it.

There are a number of factors that can be incorporated into assessing the value of a drug. The ASCO Value Framework, in fact, incorporates the clinical benefit. It includes toxicity, it includes palliative benefit if you can discontinue the drug for a fixed period of time, and it also includes patient-reported outcomes. One of the limits is that it doesn’t allow a patient to say quality of life is more important than longevity of life. But, anyway, there are a lot of different tools that are now available that can be incorporated to an estimate of the value. In the CLL space, for example, and induction therapy, you have Gazyva and chlorambucil that you would take for 24 weeks and be done versus an oral therapy that you would take until progression. So, that can be included in the patient and provider assessment to the relative value. As a payer, it’s very challenging for us to incorporate patient-reported outcomes if, in fact, they’re even reported in the trials, because we don’t have a good way of evaluating them or even comparing them.