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COTA Collaboration: Helping FDA Figure Out What's Possible and What's Not in Embrace of Real-World Evidence

Mary Caffrey
A Conversation With Chief Medical Officer Andrew Norden, MD, MPH, MBA
When it comes to generating evidence that leads to a drug approval, the randomized controlled trial (RCT) is the gold standard. The first published trial appeared in the literature more than 70 years ago,1 and over the past 30 years, the scientific community has developed the principles of evidence-based medicine,2 in which RCT results inform clinical practice guidelines.

But the problem with the gold standard, as Andrew Norden, MD, MPH, MBA, sees it, is that too many people get left out. Norden, a neurologist and neuro-oncologist who is the chief medical officer at COTA Healthcare, described a well-documented problem with current RCTs: The typical participant in a clinical trial for a cancer drug “is more often white, more often male, more often wealthy, and certainly more often healthy” than the average person with cancer.3 That means physicians need some other way to gauge how new drugs might work on the other people who come to their clinics. 

Enter real-world evidence (RWE), which is the domain of COTA, a company founded 8 years ago by cancer doctors and data scientists with the idea of harnessing the vast amounts of electronic health records (EHRs) that were accumulating, albeit in a disorganized way. COTA’s mission  is to make sense of the noise so that cancer doctors can use what the data tell them about other cancer patients just like the one in front of them. The company is known for the development of the COTA Nodal Address (CNA), which condenses patient attributes into a digital code that allows providers or payers to evaluate cancer patients with similar characteristics in patient groupings.3

In an interview with Evidence-Based Oncology™ (EBO), Norden emphasized that COTA is not looking to eliminate RCTs. But by unlocking the secrets of the data sets in EHRs, real-world data can “extend” the findings of the RCT, as Norden puts it, and offer researchers, clinicians, and the FDA insight into how drugs work in populations that don’t find their way into clinical trials.

This could mean insight about patients who are poor, are racial minorities, or have chronic conditions. “As a physician, I strongly advocate for the inclusion of patients from all those groups,” Norden said. “I think it’s a real disservice that they tend not to be [included]. Thankfully, a lot of folks are working on that problem—I want them to continue that work. But in the meantime, there are lessons we can learn about the applicability of clinical trial findings to patients who may fall into underrepresented groups in the clinical trial world.”

Congress recognized this problem in 2016 when it passed the 21st Century Cures Act, which directed the FDA to develop a framework for using RWE in the course of drug regulation.The agency has responded: It published a framework in December 20185 and in May 2019 published guidance documents on EHR data in clinical investigations and use of RWE in decision making for medical devices, as well as a draft document on submitting RWE for drugs and biologics.6

At that time, the FDA also announced it would join with COTA in a 2-year research and collaboration agreement: Starting with breast cancer, the federal regulator and the healthcare data and analytics company would create a study protocol to guide approaches to handling treatment variation within subpopulations and how RWE might be used to guide regulators.7

COTA comes to the partnership with several collaborations in hand. It has a pilot project with New Jersey’s largest insurer, Horizon Blue Cross Blue Shield,8 and joined several other technology and data sources in a project with Friends of Cancer Research.9 In July 2018, the Friends project published a white paper demonstrating several approaches to evaluating real-world end points using a scenario that evaluated patients with advanced non–small cell lung cancer treated with immune checkpoint inhibitors. The paper explored several end points—real-world progression-free survival, real-world time to progression, time to next treatment, time to treatment discontinuation, and overall survival (OS).

In the interview, Norden said that the project’s participants took different approaches, but the good news for RWE is: “We actually came to the same answers.”

According to the white paper, “The pilot project demonstrated that several extractable end points from EHR and claims data correlate with OS. Further validation is required to determine whether these end points are reliable surrogates for OS outside of a traditional clinical trial and whether they can support regulatory and payer decision making.”9

What follows is EBO’s discussion with Norden on the advancement of the CNA, plans for the FDA collaboration, and the potential for RWE (edited for clarity).

EBO: How has the CNA used data from EHRs to advance patient care to date, and how have clinicians responded to CNA?

Norden: The COTA Nodal Address is a unique way of grouping patients; in fact, we believe there isn’t another cohorting mechanism that takes into account cancer-specific information the way the CNA does. We think about it like a turbocharged ICD-10 [International Classification of Diseases, 10th

Revision
] code. It’s based on today’s conception of precision medicine, which says that you need to know a fair amount of clinical detail about any individual cancer patient to know what the right treatment is, estimate that patient’s prognosis, and predict cost of care. The CNA brings together all the attributes that influence outcomes, treatment decisions, and costs into a single digital code.

Ultimately, when the CNAs are assigned and you have 2 patients—perhaps in different geographies or with different physicians—if they have the [same] CNA, there’s no clinically proven reason those patients should be treated differently. You can use the CNA to identify unwarranted variation in treatment decisions or in costs. The information you glean from doing this analysis lets you develop an improvement plan around those things—it lets you target unwarranted variation based on specific, clinically defined cohorts that physicians understand.

EBO: How large is COTA’s network currently, and how does COTA intend to expand its network between now and 2020?

Norden: The COTA network is growing quickly. Patients represented are primarily from the East Coast, with a particular concentration from the Mid-Atlantic [region] and Florida. We are looking to expand on to the West Coast in 2019. One of the valuable aspects of COTA’s data set is that we have significant representation of patients who are treated in academic centers and community centers. We think that makes our data set more representative of the population at large. We know that in the United States, a lot of patients—maybe 80% or more—are treated in community centers. We think it’s really important that a real-world data set represent the patients regardless of the site of service. Often, we find interesting trends that relate to the way patients are cared for in one setting or the other.

EBO: Can you describe the broad outlines of COTA’s collaboration with FDA and how it fits into the agency’s commitment to incorporate RWE into decision making?

Norden: The FDA has clearly signaled in the last year or more that [the agency is] interested in the potential to use real-world data—and the evidence generated from that data—for regulatory decision making. The way I view this personally is that we have an enormous amount of information being entered into electronic medical records [EMRs].

Now, it’s a fact that EMRs were not designed from the get-go to efficiently enable analysis of data across a population of patients. That’s true, but we’re developing techniques—we at COTA and others in industry and academia—that allow one to efficiently extract and analyze it. In my view, it would be foolish not to take advantage of that data when we want to understand how cancer care is delivered in the United States. The FDA seems to be very much on board with that line of thinking.

That’s not to say that the FDA or COTA is advocating for the end of clinical trials.… That is not at all the viewpoint that COTA espouses. In fact, we think that real-world evidence, derived from the EMR and other sources, is a great complement to clinical trial data.

There’s no argument about the reality that clinical trial patients are highly selected, they are wealthier, they tend to be healthier, and they tend to be more often white and more often male in many cases than in the community of cancer patients at large. So, the value of real-world evidence is that you can look to extend the findings of clinical trials to a more broadly representative patient group. It’s also the case that there may be a small set of scenarios where real-world evidence could take the place of a clinical trial. I don’t think that’s true broadly, but I think there are some scenarios where it’s true. It may be true in rare diseases in which a clinical trial is unlikely to happen anyway because there just aren’t enough patients. It may be true in a setting where multiple drugs have already been approved and there’s no partner interested in funding a head-to-head comparison study. It may be true in a scenario where a drug has entered usage and has a very large effect size, and we can see clearly in real-world data that it’s superior to an existing agent.

There are these scenarios, but for the most part, the value in my mind of real-world evidence is that it can extend the findings of clinical trials; [it can] help us confirm that what we learned in a clinical trial is, in fact, true in patients who are somewhat different from the population represented in the clinical trial.

I think that’s what the FDA is looking to do in the collaboration with us. The truth is that today, the methods and the capacity of real-world evidence to answer important questions are somewhat immature.

 
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