Empowering Stakeholders with Innovative Trial Designs

Joseph Alvarnas, MD: You’ve raised a great question, which takes us into our next segment: this idea of trial design. You both referred to the scientific requirements in order to see whether or not a drug meets key criteria for the decision-making process. A massive phase III randomized, blinded trial may not be the best way to navigate this paradigm of precision medicine, as patients may in fact have unique characteristics that make a highly-powered trial hard to do. Some have looked at innovative trial designs, such as the TAPUR and NCI-MATCH trials, that have a different approach than the traditional study design. They promised increased patient access; a more personalized approach, which again reflects some of the differentiation that we’ve seen in the industry; and an adaptive design, all of which can provide a significant boost to the drug approval process and maybe even accelerate it in a more meaningful way.

The TAPUR study includes approved targeted agents in patients who have genomic profiles of their tumors on file. Starting with you, John, what do patients stand to gain from the TAPUR paradigm? What do you think the prerequisites are for genomic data beforehand in order to make sure that these trials are meaningful, yet at the same time without overly restricting patient enrollment?

John Fox, MD: First, in our state, we’ve been covering clinical trials for at least the last 2 decades. The ACA made that a national standard across the country—that we cover phase I through phase IV clinical trials. But the requirement is that we cover the therapeutic agent in those trials. There’s no requirement to cover the diagnostic test required for patients to get into trials. We’ve made a decision as a health plan that we’re going to cover the diagnostic test to determine if patients are eligible. It’s an end-around the requirement if you say, “We’ll cover the trial, but you have to pay the $5,000 to enter into the trial.”

There needs to be a solution to that problem, and I think some of their manufacturers are paying for those tests. But I think, “What does a patient stand to gain if there are no alternatives for that patient?” They failed the first and second line of therapy, they still have a good ECOG performance status, and they would like to continue treatment. I think that provides—not only the TAPUR and MATCH trials, but any clinical trial—another supervised option for those patients. So, I think, in general, we should support clinical trials and support enrollment in clinical trials, because that gets to the question that I asked earlier that patients, and providers, and payers all want to know—what is optimal therapy?

Joseph Alvarnas, MD: I think you’ve posed it well, which is, what is optimal therapy? Do the results from a multi-arm trial designed in this way empower stakeholders? There are a lot of stakeholders who are working to do what’s right for the patient, but also to make sure the system doesn’t harm patients and is economically sustainable. These are really multidimensional considerations, moving forward. So, do you think these trials get us closer to that trifecta of Triple Aim?

John Fox, MD: You’re looking at a payer. I would ask the clinician.

Joseph Alvarnas, MD: I’m asking all of you, actually.

Robert Carlson, MD: I think that, first of all, the patients that are enrolled on TAPUR are patients with solid tumors for which there is no great therapy. There are great therapies for some solid tumors, but they’re designed for patients who have already received those therapies and the tumor is still progressing or it’s the same situation for myeloma or B cell lymphomas. So, it’s an appropriate patient population for which there are no great options at that point. The TAPUR trial utilizes all agents that have been FDA-approved for some indication, and so we have a fair amount of confidence that the agents are safe. At least we know what the toxicity experience is likely to be, so that the patients can be educated. The physicians, in general, know what to look for. I think patients may well gain from that.

I think the challenge of a study like the TAPUR trial that has a number of small sample sizes with multiple different agents and so on—and where the assignment is non-randomized—is, what are you going to be able to conclude from the data that comes from it? And I think that those conclusions are going to, by scientific statistical criteria, be quite limited. I think what we may get from it are clues in terms of what optimal therapies may look like so that we can design trials that are larger and so forth.

One of the other concerns I had specifically about the TAPUR trial—and it’s a hard issue—is that, with a lot of the targeted therapy trials that have been done so far and some of the preclinical work, it looks like you need to target 2 or more abnormalities—targetable targets—before you see the response rates go way up. And when you then start adding 2 or 3 different agents, you end up with very, very small sample sizes, and the data become much more difficult to interpret—even if the data look better because of the sample size.

John Fox, MD: So, you’re thinking this may be more relevant to a hypothesis generation than anything else really?

Robert Carlson, MD: I think it’s clearly hypothesis generation. I’m strongly supportive of the trial, in part because these are the kinds of trials that we’re going to be forced to do in the future, and we better start learning how to do them. So, I think it’s a great trial. I don’t want to discourage anyone from going on it. I think we just have to be cautious as we start these sorts of trials in how we actually interpret the results.
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