NCDs, Part II: Evidence Development to Fulfill CED Requirements

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Tune into the second episode in the Avalere Health Essential Voice podcast series focused on the how CMS and Medicare coverage decisions define patient access. In this segment, our experts continue the conversation around national coverage determinations (NCDs)that have coverage with evidence development (CED) requirements, how FDA and CMS’s evidence questions can be complimentary, and the ways in which manufacturer evidence generation plans can address those goals, using the NCD on monoclonal antibodies for Alzheimer's disease as an example.
“If you can design a registry and design these studies to hit that sweet spot of collecting enough data to answer these research questions effectively, but minimize the burden on providers, it opens up the widest net possible of participating providers and therefore greater patient access that then leads to more robust evidence generation. ” Shelby Harrington


Mark Von Eisenburg , Consultant II, Market Access & Reimbursement

Mark Von Eisenburg supports clients by understanding translational research and science policy in a range of therapeutic areas.

Shelby Harrington , Managing Director, Evidence & Strategy

Shelby Harrington, RN, supports clients in navigating the transition to value-based care with a focus on clinical quality, strategy, and digital transformation.

If you would like to watch the video version, please visit our video page.


Mark: Hello, and welcome to another episode of Avalere Health Essential Voice. Our podcast show covers a wide range of healthcare topics. Today’s episode is part 2 in a 3-part series focused on how CMS and Medicare coverage decisions define patient access.

My name is Mark Von Eisenburg, and I’m a consultant with the Market Access practice here at Avalere Health. Today we are joined by Shelby Harrington, a Principal in Avalere’s Center for Healthcare Transformation practice.

In today’s episode, we’ll continue the conversation around national coverage determinations (NCDs) and specifically focus on fulfilling coverage with evidence development (CED) requirements after highlighting in our last session how CED operationalization can vary widely. We will also discuss some methods that life sciences companies can apply in the future to plan for this evidence generation that is fit for both regulatory and coverage needs.

Let’s start by recapping some of the details from the most recent CMS NCD decision focused on monoclonal antibodies to target amyloid beta for Alzheimer’s disease. We’ve seen 2 things in this NCD we have not seen before. The first is that the NCD covers an entire class of therapeutic drugs rather than a specific product or procedure, which happens more frequently than it has in the past. Second, CMS has outlined different evidence generation criteria to confirm clinical benefit based on the type of FDA approval that that product receives. In this case, that’s whether or not the product has used surrogate endpoints or clinical endpoints to obtain marketing approval.

Today, we’re going to take a look at how FDA and CMS’s evidence generation goals might intersect, and the ways in which study designs can be best suited to address those goals. Shelby, I’ll turn it over to you. How is this demarcated when it comes to the monoclonal antibody NCD?

Shelby: Thanks, Mark. So, this CED differentiates 2 pathways for patient access. One is through randomized controlled trials (RCTs) that occur once a drug has gone through accelerated approval and is eligible for coverage. The other pathway is the prospective comparative study requirement, which is for access when a drug has gone through the traditional FDA approval process based on a direct measure of clinical benefit.

Mark, can you explain a bit more about these 2 different pathways?

Mark: Yeah, it’s an interesting distinction, Shelby. I think at its core, it’s worthwhile to note that the CMS evidence question is similar under both paths. The method to arrive at that answer is different and for the first time, we’ve seen that the level of evidence needed to provide that answer is different.

However, the reasoning behind coverage with evidence development is the same — to verify clinical benefit of a medical product as it pertains specifically to a Medicare population. So, the reason that some products might make their way into a CED is because confirming clinical benefit with that Medicare population is still uncertain.

In the case of the data that support this particular class of drugs, extrapolating to clinically meaningful benefit in the Medicare population has not been demonstrated in a manner that CMS has found compelling, hence the CED, but RCT versus prospective comparative study are 2 divergent avenues. It’s important to note that RCTs don’t necessarily lend themselves as well to scale due to their rigor, planned enrollment, and control, as might a prospective comparative study when you’re thinking about how many beneficiaries can actually stand to benefit from being in that trial and receive Medicare coverage for their products and associated services.

So, I think that’s a call-out here because at the end of the day, that CMS question of whether coverage of an FDA-approved safe and effective product is deemed reasonable and necessary for the Medicare population remains the same. Perhaps it’s simpler to think that the goal could be accomplished with an RCT, with higher stringency, but I think the concept of prospective comparative studies, the vehicle for traditionally approved products or accelerated approved products that will transition to being traditionally approved, is an interesting one.

Can you walk us through the difference between the 2 when it comes to evidence generation and how those questions can be fulfilled by CMS?

Shelby: They are indeed very different, and they will generate different types of evidence. As you mentioned, by their design and purpose, RCTs are going to generate high-quality evidence on specific endpoints and outcomes. They’re controlling for factors and they’re following a very defined protocol so they can reasonably and confidently say that the outcomes they’re looking at are connected to the intervention.

But RCTs don’t allow widespread patient access. It’s just not logistically possible and it’s not necessarily desirable, given the purpose of an RCT. With the rigor required and the infrastructure requirements, there are limited numbers of institutions that can do this kind of work. Then even within any one institution, because of the degree of rigor and the extra data collection around it, there’s a cap on the number of participants, the number of patients that can be enrolled in any one study.

However, CMS intentionally chose this path until these drugs can demonstrate direct clinical benefit. They’re looking at this as a way to ensure what they’re calling “appropriate access,” seeing that demonstrating clinical benefit is meeting the definition from the FDA and their goal of being safe and effective by looking at the direct endpoints and taking that from what the surrogate endpoints are showing in the accelerated approval. They’re saying the access should be limited in that sense.

Once that direct clinical benefit is proven, CMS still needs answers to those questions around how these drugs work in real-world situations with diverse clinical populations over longer periods of time. That’s where the second half comes in, these prospective comparative studies. In these studies, particularly if you’ve got multiple studies that are operating under the umbrella of a registry, they have the potential, and I emphasize potential, to dramatically expand patient access and to generate really strong real-world evidence on CMS’s research questions, if those studies are carefully and thoughtfully designed.

Now, CMS has not given a lot of specifics on what would constitute an acceptable prospective comparative study outside of addressing the research questions. They state that the data may be collected in a registry, but they’re not giving a lot of details on exactly what it needs to be. They say, “A registry is not itself a study. It is a vehicle for collection of harmonized data with standardized definition of terms and that data can be analyzed in virtually any type of study or trial prospectively embedded in the registry design.”

So, there are several key points there. You can have multiple studies within this overall framework that set the terms of data collection, so that lends itself to much more widespread patient access and to getting significant data about what’s going on in real-world conditions. Again, CMS has said they’re not going to be explicit about dictating these study designs. They’re going to react to the study plans that are submitted. This is a great opportunity for researchers because they can think big and be creative on what they want this to look like without operating within very strict preset boundaries.

Something to remember, though, is that registry is a very broad term. Registries have been in existence for a long time, but they are designed and operationalized very widely. There is a lot of variation among registries in terms of type, what they do, their purpose, and their scope, therefore they vary widely in how well they expand patient access. So, that goes back to strong and carefully thought-out design of the studies and the registry itself.

Mark: Very interesting insight, Shelby. I immediately think about the myriad ways in which a prospective comparative study or a registry could manifest but at the same time be anchored to the key evidence question that CMS has brought, which is, “Are these drugs reasonable and necessary for use in a Medicare population? Are they producing some type of measurable clinical benefit to these Medicare patients?”

So, what is it about the attributes of a prospective comparative study, or studies, that might help CMS arrive at an answer to this question in a potentially more compelling way?

Shelby: In terms of design and how prospective comparative studies, particularly those in a registry, are better suited than RCTs to generating this real-world evidence, RCTs have a lot of structure and rigor, which is not conducive to seeing what would really go on under real-world conditions. Registries tend to be observational. They’re collecting data about a patient population as they’re going through the care journey that they would have gone through anyway and observing their experience and the outcomes without directly intervening. So, you’re getting a much wider set of clinical scenarios. In the case of Alzheimer’s, this may even include patients that choose not to undergo pharmacological treatment for their illness.

Another factor is that registries tend to be ongoing. They don’t have a predetermined date or a predetermined enrollment threshold at which point the registry stops. That provides better visibility on how benefits and harms change over time. With an illness like Alzheimer’s that has a slow progression, the longitudinal view of a large study population and looking over a longer period of time is going to be more helpful in understanding the effects of treatment.

If you have an ongoing registry as that overarching data collection framework that standardizes your terms and what data you’re collecting, and then you have multiple studies embedded in that registry to answer specific research questions, the studies themselves can be running over different lengths of time and with multiple points at which they report out results.

Then when we look at increasing patient access, which is going to get into what CMS is asking for with broader community settings where treatment is being delivered and a diverse representative patient mix, it’s really important to have that bigger patient base to which this study type lends itself.

What’s really key as well, and this goes back to our point about making sure that it’s designed and operated carefully, is getting a large number of different types of physician practices to participate. Providers are the gatekeepers. Medicare patients can only access these drugs through providers that participate in a CMS-approved study. When we look at registries and how widely they can vary and how they operate, the design of the studies can be a major factor in whether providers choose to enroll. If you look at existing registries, some of them require manual data collection. The practices may have to invest a lot of time and possibly even hire additional staff members just to manage that component of data collection. Some registries have subscription or enrollment fees that a practice has to pay to participate. Some require specialized software that a practice has to purchase. So, the study designers really need to think about these potential barriers to provider participation and ensure that the way that they design this registry and the associated studies doesn’t require so much effort for providers that they just decide not to participate.

If you can design a registry and design these studies to hit that sweet spot of collecting enough data to answer these research questions effectively, but minimize the burden on providers, it opens up the widest net possible of participating providers and therefore greater patient access that then leads to more robust evidence generation.

Mark: Interesting, Shelby. It sounds to me like this type of study design is not something that pops up overnight. We’re still at least a few months away from seeing any traditionally approved drugs that are required to move through this prospective comparative studies path when it comes to this monoclonal antibody for Alzheimer’s disease NCD. But surely there must be some implications here for life sciences companies that are looking at the best ways to generate real-world data and turn that into real world evidence. Is there anything from a timeline perspective that companies could be doing now? Engagement, perhaps? We’d love to hear how timelines factor in.

Shelby: Yeah, you are absolutely right when you say it doesn’t happen overnight. I think drug manufacturers are focused right now on their post-accelerated approval RCT strategy for coverage for generating data to demonstrate clinical benefit. They need to be thinking in parallel about their strategy post-traditional approval because that’s really where the patient access opens up. Building a registry takes a lot of time, it takes very careful thought because you’re building something for the long haul. So, you need to really talk to providers and figure out what their needs are and how you can embed this work into their existing workflow. How can they receive value out of participating in these studies? Think about it from a user-centered approach.

There’s also a strong likelihood that there will need to be partnerships with external organizations like a technology vendor or an analytics vendor to handle some of the technical operations of this. Those types of partnerships take a long time, too.

Then, of course, this also needs to happen within the constraints and the requirements of working with the agencies, with CMS and FDA. You’ve got to understand their requirements for traditional approval so that they can achieve that and get out of the RCT path into this study path.

Mark: Totally. This is something that we discussed briefly in our previous podcast episode in this series, but you’re getting to this interesting point that despite FDA and CMS having complementary remit as sister agencies in HHS, their roles are separate and distinct. This recent NCD decision has shined a light on how, moving forward, there might be an opportunity for product developers to plan their evidence generation strategy to answer both the regulatory and the coverage goal, or to at least have both of those ideas in mind early. In the case of the NCD that we’ve discussed today, it applies to both the accelerated approval and the traditional approval routes.

Keep in mind that when a manufacturer sponsor receives their FDA approval letter, there is typically some type of post-marketing commitment, regardless of whether you’ve gone through accelerated approval, like a confirmatory trial to deliver on the effectiveness of the surrogate endpoint, or if it’s something that’s more run-of-the-mill, post-marketing commitment to study safety in a longitudinal manner or to look at product performance in the new population, for example. These are standard requirements from a regulatory standpoint.

So, this ongoing evidence generation and the thinking that’s required to be proactive when communicating with FDA and CMS, potentially in tandem, is certainly an area that is growing and has received some attention from this NCD working to have studies stood up in a timely manner so that patient access to medicines can be maintained or unhampered. Obviously, that’s the goal. We’ll be looking to see if business changes, statutory changes, or regulatory changes might affect this process moving forward.

Our next podcast episode will pick back up with this discussion around patient access, taking the FDA approval pathways and coverage assessment guidance on Medicare Part D and starting to look at how potential policy and market catalysts 3 to 5 years out can help stakeholders think through opportunities and risks at those junctures. That session will be hosted by my colleague Kelly George, who heads up the Regulatory Strategy and FDA Policy practice, which is within Market Access at Avalere, as well as Ryan Urgo, who’s a Managing Director in our Policy practice. Hopefully, you’ll join us for our third episode.

Thank you, Shelby for joining me today and thank you all for tuning in to Avalere Health Essential Voice. Please tune in for the next episode in the series, as well as other episodes. If you’d like to learn more, please visit us at our website

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