Q&A with Richard L. Schilsky, MD: Gains Against Cancer, But Enter ‘Financial Toxicity’

Why did you pick oncology?

Well, it’s a long time ago now that I made that choice. I guess there were several influences. One was a family experience with cancer. My grandmother developed, and subsequently died from, metastatic breast cancer. Also, when I was in medical school, I had an opportunity during one summer to spend some time working in the radiation oncology department at NYU Medical Center — I went to medical school at the University of Chicago but lived in New York City — and that gave me experience with physical examination and speaking with cancer patients. I also had an influential mentor in John Ultmann, who was an iconic figure in medical oncology and on the faculty at Chicago. So, it was all of those things together.

Richard L. Schilsky, MD

When were you in medical school?

I graduated in 1975.

In that era, you didn’t have success stories in oncology, right? Wasn’t it profoundly depressing?

You know, I’ve never at any point found being an oncologist to be depressing. I mean, cancer is a very serious disease, and certainly 40 years ago when I was in medical school, it was not only serious, in that most people died from it, but it was also disfiguring — and painful.

That said, the job of the oncologist was to make that experience as favorable as it could possibly be for a patient. It’s not like we had nothing to work with. We had surgery. We had radiation therapy. We had a number of chemotherapy drugs, many of which are still in use today. What we didn’t have, to any great extent — and which we have a lot of today — are supportive-care medications — the antinausea medicines, growth factors to support blood counts, and other kinds of medications that make the experience of getting cancer treatment far easier for patients than it used to be many years ago.

In the telling of the story of cancer, have supportive medications been overlooked, maybe?

I would totally agree with that.

I’ll tell you a quick anecdote. In the latter part of the 1970s, I was training at the National Cancer Institute. And the drug cisplatin was just coming into use in treating testicular and ovarian cancer, and we used it often. That was a drug that produced profound, profound nausea and vomiting in patients, and we really had no effective antinausea medications. So, we’d have these poor patients in the hospital for a week at a time. They’d be on IV fluids, they couldn’t eat; they’d be sitting with a bucket in front of them, retching continuously. It was an awful experience.

Flash forward 35 years, to a few years ago. I was seeing a patient in our infusion center at the University of Chicago with one of my fellows, and the patient was sitting there, in a chair, with the IV going, watching television and eating a sandwich. I asked him how he was feeling, and I looked up to see what the chemo regimen was that he was getting, and it was cisplatin. The same chemotherapy drug! But now, with the powerful antiemetics that are used to pretreat patients, the patients are comfortable, no nausea, eating lunch, and having their chemo. It’s a completely different experience for the patient.

This publication deals with the cost of care. Did cost of care ever come up early in your career?

Never. Part of that is because I think it just wasn’t really something that doctors and patients customarily discussed. Part of it is that I spent my career at an academic medical center at the University of Chicago. The doctors didn’t buy drugs, we weren’t necessarily aware of what the cost of any of the treatments were. Those were all functions that the medical center dealt with. But, even if we had been more knowledgeable about what the costs were, I don’t know that we would necessarily have factored that into the discussion in the old days, because the costs were not nearly as burdensome to patients as they are today.

Do you remember the first time you had a discussion where cost was mentioned?

I couldn’t place it in a particular year. Certainly, you know, patients have always asked questions about the likelihood that their insurance would cover the treatment or the tests. And, of course, the doctors usually couldn’t answer that. We would just say you have to talk to your insurance company.

I think doctors became more aware of these issues about 15, 20 years ago when more and more insurance companies began to put preauthorization programs in place. All of a sudden, doctors had to justify why they were ordering a test, or why they were using a particular treatment, calling up and getting permission.

At that point, it became clear that somebody was paying attention to the cost, and trying to use the preauthorization mechanism as a way of constraining the cost to some extent.

That’s ’90s managed care. Did you experience that? Did you resent it?

I didn’t experience it personally. Again, where I worked at the University of Chicago, we didn’t practice in a managed care environment. And it was in the Midwest where managed care was not necessarily as prominent as it was in California.

I’d like to talk about drug development and drug development costs, and also discuss value-based care and payment. Cancer treatments seemed to change in the 2000s with Gleevec and targeted therapy. Do you see that as an inflection point?

I think so. In many cases, drugs had been developed with very limited information about the mechanism of action or what the target of the drug was. It was very much an empirical process. Post-Gleevec, the paradigm has completely shifted to where the first thing is to understand the biology that’s driving the cancer, understand what the critical genomic or molecular pathways are, and then, develop pharmaceuticals that can, in some way, interfere with those pathways. In my mind, that’s what has led to not only more efficient drug development but the ability to develop drugs with companion diagnostics, so that one can identify the patient population most likely to benefit from the drug.

But aren’t we seeing a lot of resistance developed to these drugs, and therefore, they haven’t necessarily lived up to their billing?

Sure, but that’s not an indictment of the approach. I think, in a sense, the fundamental challenge of cancer is that we have not yet been able to overcome cancer’s ability to evolve and change. It’s a bit like saying the only way we’re going to master cancer is to master evolution, because, in a sense, cancer represents evolution at the level of a single individual, rather than at the level of a population.

The fact that the targeted therapies, we now realize, may not have the long-term impact in many cancers that we had hoped — that doesn’t mean that the approach of developing targeted therapies is wrong. It just means that the biology is more complicated than we recognize.

How should drug development and clinical trial design change to reflect molecularly targeted therapy?

We tend to hold the randomized clinical trial up as something that is absolutely sacrosanct. There’s no question that the randomized clinical trial is a very powerful tool in clinical research. It’s particularly necessary when one is trying to evaluate what may be only small differences between treatments. In those circumstances, to be confident that any observation is not due to bias requires a randomized trial.

But if you’re looking for big treatment differences, you may not need a randomized trial. If you have a well defined, historical control population and you know the natural history of a disease, and you have a new treatment that dramatically alters that natural history, the likelihood is that what you’re observing from the new treatment is related to the new treatment and not due to bias. You may not need a randomized trial in that setting.

And, in fact, we are seeing more and more drugs that are getting approved by FDA based on results of nonrandomized trials, or trials that have historical controls, or trials that are just small, randomized phase 2 studies, that don’t have the statistical power of a full-blown phase 3 trial. Or even, in some cases, the FDA approving drugs based upon a phase 1 clinical trial, where the study population is large enough to draw conclusions both about safety, the dosing, and the efficacy, all in a single trial.

Are you thinking of a particular drug approved after just a phase 1 trial?

Pembrolizumab — Keytruda — is a recent example of a drug that was FDA approved based on a phase 1 trial.

Do you think this is a good thing?

It’s good and bad. It’s a risk–benefit assessment. So, the rapid introduction of drugs into the marketplace is certainly good when there’s high unmet medical need and a drug seems to be clearly efficacious and safe.

On the other hand, one of the consequences of these smaller trials is that the amount of data that’s available, both to regulators and to clinicians and patients, when the drug is introduced is much less than in the past.

Now, we have drugs that are being introduced where don’t really know what the clinical benefit is because the endpoint in the trial may have been response rate, or progression-free survival. We may not have the more definitive endpoints, like overall survival. Sometimes, drugs will be introduced with limited safety data sets, and the safety data are only applicable to the patients who participated in the clinical trials.

So, there are those who would argue that the FDA is doing a bad job by putting drugs out there without definitive proof of benefit and with limited safety data. That exposes people to risk. On the other hand, many people would argue that the FDA is doing a great job by getting very promising new drugs into the marketplace as quickly as possible so that patients have the opportunity to benefit from them.

The challenge that regulatory authorities are facing, not only in the United States but also in Europe and elsewhere around the world, is “how much risk are we willing to take that the drug might not actually pan out and let it get into the market early?” versus “how much risk are we willing to take that we’re withholding a potentially very effective drug from patients who need it by delaying the regulatory approval until we assemble all the necessary information?”

It sounds like it’s been a conundrum that’s been answered by the FDA and other regulatory authorities: Less data premarket but ramp up post­market surveillance. Do you think the current system is working?

I would argue that it’s working. A large number of drugs has been introduced in the last decade, and very, very few of them have been removed from the market. You can count on the fingers of one hand the number of drugs or indications that have been withdrawn from the market in the last 15 or 20 years in cancer.

What do you think about changing trial designs — the basket trial, for example?

The basket trials are mostly screening trials, screening for drug activity. And they are necessitated by two or three things. One is that there are common genomic abnormalities that occur across multiple cancer types. The second is, in almost all cases, those genomic abnormalities are rare. So, it’s extremely uncommon to find a mutation that occurs more frequently than, say, in 10% of the population in any tumor type. And in most cases, these mutations occur in 5% or less of the population.

The third issue is that we’re not certain whether each mutation has the same biological impact in each tumor type. So, in order to be able to learn all these things, you need a different approach to doing the clinical trials, because there simply is not enough patients, enough time, enough money, to study every rare subtype of every cancer, with every potentially effective drug using the traditional clinical trial design. So, the basket trials have emerged as a strategy.

I think we will see, at some point in the future, a drug whose approval is based just on the presence of a mutation in any type of cancer, without necessarily specifying the cancer type.

But one of the challenges of that approach is that different genomic abnormalities don’t have the same impact. The classic example is BRAF mutation in colon cancer. BRAF mutations occur in about 5% of colon cancers, and yet, those tumors don’t respond to BRAF inhibitors, even though it’s the same mutation that occurs in melanoma, where BRAF inhibitors are highly active. So, that observation has led people to take a couple steps backward and say, “Wait a minute. We could be doing some harm here if we assume that every targeted drug is going to work against every tumor type that harbors the target.” So, the biological context is important.

I think we still continue to sort through that. Until we do, we’re probably not going to be ready to just move wholesale to a new molecular categorization of cancer.

The high cost of drugs is increasingly being shifted to patients, in the form of higher deductibles on their insurance premium or higher copayments.

Let’s shift to the almighty dollar discussion. Dr. Kantarjian at MD Anderson, who has been an outspoken critic of high drug prices, says that high prices are harming patients. Do you agree?

Yes. What we hear and what we see documented increasingly in the literature now is that the high cost of drugs is increasingly being shifted to patients in the form of higher deductibles on their insurance coverage or higher copayments. Even if copayments are not changing, the absolute dollar amount that a patient has to pay is increasing. If you have a 20% copay and your drug costs $100 a month, you’re paying $20. If you have a 20% copay and your drug costs $10,000 a month, you’re paying $2,000. We’re seeing a lot of reports of patients describing how they have to take out second mortgages, they can’t afford to pay their rent, they can’t afford to send their kids to school, they have to modify their medication doses, they don’t get their prescriptions filled on schedule, or they take their medicines every other day instead of daily. All sorts of things have now been rolled up into this description of the financial toxicity of treatment that patients are increasingly experiencing.

Do you think the pharmaceutical companies are pricing their drugs too high?

Well, pharmaceutical companies are pricing their drugs at whatever price the market will bear. But what is the right price? Of course, that’s the real challenge — defining the right price, given what the drug is delivering to the patient. One of the reasons that ASCO came out with our value framework, which we published at the end of June, was to try to show a way of thinking about this that can help doctors and patients evaluate medications. What are they actually getting for whatever the cost of the medicine is? We don’t have a normal consumer market dynamic in medicine and health care. If you go to buy a car, you pretty much can figure out what you’re getting for the $75,000 car versus what are you getting for the $25,000 car. But in medicine, the answer is not so clear cut.

We have no mechanism in the U.S. either to evaluate, or really negotiate, the prices of drugs based on any sort of value system.

One solution would be allowing CMS to negotiate price like the government does in other countries, where health care is supported more fully by taxes. Is it time for CMS to start negotiating prices?

I think that is a possible solution that we need to think seriously about. The problem in the United States, to some extent, is that there are no constraints on the cost of care at almost any level. Insurance picks up a lot of the cost, and the only thing the patient knows is what their out-of-pocket expenses might be. Doctors, in many cases, in the current reimbursement system, are actually incentivized to prescribe the more costly medicines, at least for the infused cancer drugs. And the insurance companies, in a sense, view the increasing cost of drugs as a pass-through.

And, of course, we have no mechanism in the United States either to evaluate, or really negotiate, the prices of drugs on the basis of any sort of value system. As you point out, most other countries of the world, and certainly most countries in Europe, have government agencies or government-appointed third parties that do some sort of value assessment.

We don’t do any of that in the United States. So, the result is that the drug companies come out with a price that is similar to, or slightly more than, the last drug that was introduced. We have no effective way of pushing back on that.

The argument has been made that Medicare, which is the largest insurer in the country, and certainly the largest insurer of cancer patients, could help to constrain some of these costs if it was given authority to negotiate drug prices. That would require an act of Congress, literally, to allow that to happen. And then, it would remain to be seen the extent to which those negotiations would successfully drive down prices.

Wouldn’t ASCO be in a position to advocate that it’s time now for CMS to start to negotiate?

I would only say, at this point, we’re well aware of the arguments that are made on both sides of this issue, and we are thinking through the issues, trying to determine whether this is something that we wish to actually vigorously advocate for.

You’ve come out with a value-based framework, NCCN is working on getting costs into its guidelines, Peter Bach at Memorial Sloan Kettering has come up with an online tool. Aren’t we going to end up with a confusing situation with multiple measures of value out there?

I guess I would put it this way: I think that all these efforts are important, and they’re important mostly because they indicate that we are ready as a profession — and, hopefully, as a society — to deal with these issues. I certainly wouldn’t claim that ASCO’s approach is necessarily the best approach, or the right approach, or the only approach. We’ve got lots of feedback about it. We will likely make some improvements to it as time goes by. I’m sure NCCN will get lots of feedback. You didn’t mention ESMO — the European Society of Medical Oncology. They also have a value framework that was published this spring. So, it’s a global issue. It’s unlikely that any one of them is perfect. But all of them signify both a willingness to elevate the discussion and are putting forward approaches that can be improved and modified.

I’ve read some criticism that these value-based efforts put a price on life and that people’s insurance will determine the sort of care that they get.

There’s nothing in the ASCO framework that is stimulating a change in coverage policy that we know. And anything that the ASCO framework describes with respect to how patient cost might be calculated is based upon the prevailing coverage plans.

Variances in terms of copays, and deductibles, and tiered pricing — all of that stuff is happening right now. Remember, insurance companies and others are coming out with clinical pathways, and clinical pathways typically incentivize the use of less expensive therapies. Arguments have been made that those approaches are also limiting patient choice, limiting care options, and things of that sort.

So, what ASCO has felt, and we firmly believe, is that a discussion between the doctor and the patient about treatment options needs to include a discussion about value and cost. You need to know if a drug is going to cost you a certain amount out of pocket per month, how much more benefit that drug is producing or is likely to produce. Or, what sort of toxicity profile that drug has compared with another option that could be available to you. You need that information to help you make the best informed choice given the nature of your disease, the nature of your other medical illnesses, your personal goals, your family circumstances. It is a multidimensional conversation. But the dimension that has been absent for so long has been the opportunity and the ability for doctors and patients to talk about value and cost in a meaningful way. That’s what we are trying to accomplish with the value framework.

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