Director of Strategy and Market Access, Research Health
Andrew has extensive involvement with CAR-T and gene therapy pricing and reimbursement dynamics based on 5 years working at the NICE assessment processes for such products in the Oncology and Highly Specialized Technologies (HST) managed entry and patient access schemes (PAS). He is knowledgeable about guidance and decision points related to the following CAR-T and Gene Therapies that are already approved and pried and reimbursed using methods of innovative contracting.
Section 1: Current Landscape
1.1. How would you describe the current market access landscape for CAR T-cell therapies?
The situation certainly in the UK market for the couple of CAR Ts that are currently in the system, I think was neatly summarized by the sort of reasons why the committee made their decisions on the NICE appraisals and that the system offers considerable promise.
The caveats to that are that there’s no head-to-head with the current standards of care in the UK market, and the long-term outcomes still carry a degree of uncertainty. So that’s why in the UK market, they’re in a Cancer Drugs Fund. If you look at other countries in Europe, for example in Italy, the agreement and access are based around the performance i.e., how well the patients do. The understanding is that AIFA has assessed it and said, “If a patient is surviving and doing, the outcomes are good after certain periods of time, then payments are made.” Now the degree to which that’s established fact, I’m uncertain about. Those are what I’ve heard in various fora. In France and Germany, they are approved with similar kinds of a caveat to the UK in terms of there’s some uncertainty about the outcomes.
In terms of the evolution of CAR T therapies, there are two elements to that. One is the actual appraisal against the evidence and the other part is more political, and that’s a desire to offer these advanced services in the UK. At the level of NHS England, the specialized commissioning services, then there is a desire to come to agreements with companies and to gain access and to build the capacity within the healthcare system to offer these innovative approaches in oncology. With a view to being able to provide advanced therapies for patients not only with the particular types of cancers that we currently see, but maybe going beyond that. There’s a number of centers that have been tooled up, so to speak, to deliver advanced therapies, typically based around the sort of STEM cell technologies and STEM cell centers.
Now, the use of the Cancer Drugs Fund to fund the current two CAR Ts in the sort of two- and a-bit indications is where we’ve got to; others will be reviewed in time. Now the timings, were pretty much picked up shortly after getting approval from the EMA. There was a bit of a delay, and the Cancer Drugs Fund is going to monitor their compliance I believe in 2023. So, there’s still some time to collect the long-term evidence. Access to the technologies is very, I want to say tightly controlled but what you see in the Cancer Drugs Fund is a sort of ongoing real world evidence collection process, the NHS is using this and using the technologies and at the same time collecting the evidence. As a consequence, the access criteria are quite strict and in line with the marketing authorization, and those decisions are made by a central steering group. Now that is going to prevail until 2023 when NICE will review what’s happened in the NHS and come to conclusions about that in terms of subsequent agreements for future access.
1.2. What are the current types of reimbursement schemes used for CAR T-cell therapies?
NICE has patient access scheme systems that are overt to an extent. In that, you know what’s been in place. If it’s a simple discount, then the actual amount counted is commercially confidential. In the Cancer Drugs Fund, they’re typically covered by and what are euphemistically termed, comes to commercial access agreement.
Now the actual terms and conditions of those access agreements whilst the drugs are in the Cancer Drugs Fund remain commercially confidential, so it’s really difficult to say precisely what terms and conditions have been agreed with the companies. Obviously, there are people in the company and there are people in NHS England who know what those terms and conditions are. But for an outsider, and you don’t want to include the majority of the people who might be working in that field, the details are unknown.
There is the potential of something like an Italian arrangement where the argument goes in Italy, and I don’t know how true this is, that is you get one payment when you have the therapy. You get another payment if you’re still surviving and showing progress, I think it was 18 months and another at three years. So, if you walk out of the hospital at three years, the company’s had all these payments that are getting closer to whatever list price they’ve agreed in Italy.
The Italians, and particularly in oncology they’ve got quite a wide use of registries to track performance and pay by outcomes and sometimes the pharma companies get quite an exposure before they get paid. If you go through the background of outcome-based schemes in NHS England, then there isn’t an enthusiasm for them until quite recently and that’s based on the fact that the patient access scheme system tended to gravitate towards simpler schemes, such as just a basic discount. Now, the rationale behind that is the administrative burden and tracking performance of any particular outcome or any particular aspect of a patient’s progress. Typically, if you didn’t match that to something the NHS was already doing, then your chances of getting an outcome-based scheme through patient access schemes liaison unit were close to zero.
Some of them did get through, I can vouch for that, but they didn’t see the light of day. Because once that scheme had dropped into the technology appraisal process, it didn’t deliver the outcome in terms of an approvable ICER. Therefore, the only solution left to the company at that stage, which is in the rapid review stage, it’s a simple discount. So, if your scheme gets approval, but fails to deliver the right level of discount, you still fail and you have to go to a simple discount.
1.3. How successful have CAR T-cell therapy market penetration attempts been?
I mean the opportunities and the degree to which the NHS will support new CAR T therapies, it’s typically driven by efficacy and demonstrable efficacy. So the greater the true efficacy of the product and how well that’s supported or modeled in the medium and longer-term, and the closer it is to a comparison with the standard of care, the more likely it is that NICE will approve it. That’s where you see the current therapies in the Cancer Drugs Fund with some uncertainty around them because those things were the question marks NICE had. So, in terms of acceptability and ability to get them in place. The winge you get is that you’ve got two different onboarding systems. Those are quite complex, and we’re getting to grips with them.
However, let’s say we finish up with 10 different CAR Ts, all from different companies all bringing slight variations to those onboarding systems. That gets a bit complicated, and it gets difficult for the clinician. There’s a degree of standardization into that process which always is relevant between and within and across indications, companies, etc. It is something that might be useful for a future cross-company cooperation arrangement. In terms of NHS providing and paying for, the better efficacy that you can demonstrate from the robustness of that, and the per order acceptability and the indication for that. a.
Section 2: Future Landscape
2.1. Which oncology indications and settings could benefit most from CAR T-cell therapy in the future?
I believe that’s very much on the horizon, and companies are working on that type of technology furiously as we speak. So, I could see the indication list for liquid tumors expanding. The various discussions with early-stage, exploratory discussions I’ve had with companies, indicate that there’s perhaps a little way to go before these become viable treatments.
With regards to inpatient and outpatient settings, whenever you’re dealing with new technology, the desire is to keep the patient under close observation and have them close to centers where if there is a side effect or a sort of immune response, then you can deal with it. Having a crash team nearby, rather than having them in an outpatient setting which might not automatically allow you to have that sort of intense responsive approach available quite so readily. So, the initial treatments are typically all going to be impatient. The potential to deliver it through outpatient will be supported by experience. The more patients that go through the system, the more relaxed clinicians become with the treatment option. The more likely an outpatient delivery might be, become a practical opportunity.
It is likely to be reserved for those fitter patients and those patients who might live closer to the hospital where they’re getting their treatment. So, if I’m going to be treated in an outpatient setting and then go home if my home is a long distance away, then I’ve got an awful long way to go to get back and get the care and someone might be an inpatient. Whereas if I just live around the corner, then I can easily get back in if something goes wrong.
2.2. How are pharma companies looking to facilitate greater market access of CAR T in major healthcare markets?
I think the outcome-based approach offers great merit. In terms of the true potential of CAR Ts is towards, and I’m going to use the word, advisedly curative. If I can have something that keeps my patients in remission for long periods of time, then that’s something which payers are going to be very interested in paying for, and then that’s going to make a big difference. What might companies contribute? I’ve already mentioned the onboarding systems. Now those onboarding systems if companies could cooperate in some respects, not in collusion or anything like that, so you still have the compliance with competition laws but towards introducing some form of standardization between them, that could make a great contribution. In terms of supporting the actual practical delivery, then yes, there are opportunities there. The final approach might be actually, “We’ll just deliver this service for you.”? and that scenario has potential. You just say, “Okay, we will set up a center and deliver CAR T therapy for you.” and the economies of scale with one national center, let’s say in and around London, could be sufficient for the NHS to buy that.
2.3. What are the issues around centralized CAR T manufacturing processes?
The UK has taken a degree of decentralization into its approach, and there are centers in the main population centers around the UK. I believe that could become even more decentralized, with time and greater familiarity and simplicity in access. Now, the opportunity to make this like a mobile MRI or scanning center and take it around the country presents itself. Now that may be pie in the sky, but that could be a way of getting out to the more extreme communities but given that it’s not just a one-stop-shop, you have to go in and have your assessment done, cells were taken and your cells reinjected, it’s complex. You would have to go there and then go back again, but some form of remote access is possible. That the NHS is very much committed to equities, and geographical equity features but there’s travel involved however you look at it. Whether you’re coming from Cornwall to Bristol, for example, or from one part of London to another.
2.4. How will reimbursement models evolve to better accommodate costly CAR T-cell therapies?
Given the potentially high cost, but the option of delivering a very good outcome, I think there are potential other approaches that could be used. Crudely, you could go for a price-volume. You don’t have to go for, “We’ll only get paid for those that work.” You could say, “Well, it’s worth trying with lots of other people,” so somewhere between those two extremes. As I mentioned before, the companies could be more proactive and think, “Well, we might take on delivering this as a specialist service.” and you could, you’re then into contracting per head; those options are there. The specialized commissioning team at NHS England, the likes of Blake Dark and his commercial medicine team, they’re stepping up their game in terms of innovation and contracting. There’s a document coming out soon called the commercial framework. Which broadly speaking says, and here I’m paraphrasing a very comprehensive piece of work that, “The greater the performance, the more likely the NHS is to reward companies.” Particularly in areas of considerable unmet need and, “How am I going to address innovation?”
However yes, “The more innovative and the more you’re addressing an unmet need, the more likely NHS England are to reward,” I think is a very broad summary of what that document is aiming to achieve.
2.5. What are some of the issues around potential allogenic CAR T-cell therapy?
Delivering a patient’s own cells is a bit of a challenge, and that can sometimes rule some patients out. The allogenic route as long as it could be safely delivered and not result in a catastrophic immune response could be viable. As long as that is going to be a practical proposition, it isn’t going to involve huge amounts of immunosuppression or other therapy to prevent some sort of anaphylactic shock or some other very adverse reaction. I think there’s potential there, particularly for patients for whom their own cells are not to be a viable proposition. Obviously, the regulatory hurdles would have to be met and at the end of the day, safety comes first. The technology would have to be proven and proven in patients for whom they could be quite vulnerable, they could have all sorts of other comorbidities. So that the requirement would be to get through over those high safety hurdles and to demonstrate that it’s going to work effectively for all-comers. Particularly where we came into this thinking that it might be appropriate for the very unwell patients, and the last thing on earth you’d want to do is give them a further challenge immunogenically. It would have to meet those very high criteria for safety, through all the regulatory hurdles.
The regulations sort of already exist but they would need to be enhanced and made appropriate for each indication or a general class of indication might be a better way of putting it and where you might start crossing borders in terms of classes, indications, etc. There would need to be a review at that point so, I don’t think this is an insurmountable hurdle, but I think it would very much be on the table.
2.6. What are the roles real world evidence and patient recorded outcomes can play in CAR T-cell therapies?
As a payer, you take part in a lot of ad boards and discussions. The common theme you hear is that its overall survival, overall survival, and overall survival. So, those deliver the hard QALY gains. It’s very good to know that the patients, they’re having a better experience and the PROs are moving in the right direction but when it comes to whether the patients are alive or dead, those are the biggest movers. Now that’s a bit brutal but at this, in these kinds of indications, overall survival is the key driver, supported by progression-free and then response rates. So, once you get into the finer nuances of the indication, then yes, patients having a better experience on one treatment compared to another does move the needle a little bit. However, it’s marginal compared to the difference between overall survival of five months, for example.