Accelerated Approvals in Oncology: Benefits, Risks, and the Way Forward With Dr. Jason Mouabbi, Dr. Ross Maclean, and Michael Glover

In this interview, Dr. Jason Mouabbi, OncData Editorial Board Member and Breast Medical Oncologist at MD Anderson Cancer Center, speaks with Dr. Ross Maclean and Michael Glover about the debate surrounding accelerated FDA approvals, including their benefits, risks, and ways that physicians, patients, pharmaceutical companies, and the FDA can collaborate to maximize the impact of accelerated approval drugs.  

Jason Mouabbi, MD: Hello, everyone. I’m Jason Mouabbi. I’m a Breast Medical Oncologist at MD Anderson Cancer Center, and I’m a member of the Editorial Board at Oncology Data Advisor. Today, I have the pleasure to be joined by two guests—Ross Maclean, Executive Vice President of Precision Health Economics & Outcomes Research and the Head of Medical Affairs for Precision Value & Health, and Michael Glover, Partner at Qinexa Consultancy, LLC.

Today, our topic is very, very interesting. It’s about oncology drug accelerated FDA approvals and the big debate surrounding the FDA’s decision on which oncology drugs are deemed noteworthy of such approval. It’s really important, first, to define what an accelerated approval is. My first question is a little bit loaded, but what is accelerated approval, and what is needed to obtain such an approval? We can also go into the weeds about how it differs from a regular FDA drug approval. And for physicians who see patients on a day-to-day basis, should they view an accelerated approval differently than a regular approval?

Ross Maclean, MD: Thank you, Dr. Mouabbi, Ross Maclean here. It’s a great pleasure to be here today.

At the end of the day, the use of any and all treatments is a function of the benefit and risk known about that treatment. When one thinks about accelerated approval, it’s the regulator trying to balance the demand from the provider for treatment options, the excitement from the patient about innovative and possibly even curative treatments, and the conservative, data-driven, fact-based requirements of the regulator to make sure that the drug is safe and there is demonstrated efficacy, to the best of their ability. That’s a tension in any and all drugs. It’s not just a cancer thing; it’s in all drugs, all treatments.

Accelerated approval emerged in 1992 as a means address this tension in areas of huge unmet need, where the very act of seeing a clinical trial program through to its classical or conventional completion would add many years to the potential approval timeline. In that time, possibly dozens, hundreds, or thousands of people could have not had the chance to receive access to that treatment. I think it wasn’t a response to consumer pressure; it was a response to the natural tension to bring innovation to patients, which we know is something near and dear to the American people, yet at the same time balance with the need to generate the right data to prove that the drug is safe and efficacious. That’s the origin of it.

With any good intention and good idea, clearly there are challenges, and I think what we’re witnessing right now are some of the challenges that are emerging after about 30 years of having this process in place. But we’ll get into that in a minute. Mike, your thoughts?

Michael Glover: Well put, Ross, from a pharma perspective. If you think about where the roots of accelerated approval came from, it really stemmed from human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). This was a high unmet need with very few potential solutions to that disease. That’s where it was born, as Ross said, in early 1990s. Now, we’ve seen accelerated approval used for many things, not just oncology, but other diseases. Then more recently, we’ve seen it used in Alzheimer’s.

We have a process where the FDA has recognized that we have a high unmet need, we have a small population, or we have a disease that doesn’t have any potential treatments currently or is very rare. As Ross said, a normal clinical trial, particularly in a rare disease, may take up to 10 years to get to its conclusion. The decision and the discussion is, “Well, how do we get this treatment to patients quickly whilst we continue to collect data?” I think that’s where some of the potential misalignments in incentives are. We’ll get into that later, but that’s the origin of where the accelerated approval process comes from.

Dr. Mouabbi: That’s very interesting, and those are some great examples. The next question is, can you provide a bit of an overview about why this is controversial? Why do we always think about accelerated approvals as controversial? I can tell you as a breast oncologist, I remember the days of bevacizumab when it first received accelerated approval and everybody was using it. Then a few years later, it failed to get the full approval and it was suddenly taken off. I lived through that a little bit in breast oncology, but I understand there are other examples out there about why it’s controversial. What are some of the key regulatory issues that have sparked that debate within the industry and among stakeholders?

Mr. Glover: There are some good examples, and Ross and I pulled some discussion topics together. I was just looking at some interesting information the other day. If you look at Medicaid, for example, 9% of Medicaid spend is on accelerated approval drugs, but it accounts for 0.4% of the total prescription levels. There’s already an imbalance between what’s being spent and what the actual numbers of patients are. You talked about bevacizumab, and there are other examples of drugs that have been on the market for eight, nine, or 10 years and still don’t have a confirmatory trial but are being paid for and being used by physicians. I think that’s where we have some of the controversy to say, “Well, actually, who does the risk lie with? Does it lie with the pharmaceutical company, does it lie with the FDA, or does it lie with the physician or the patient?”

If you’ve got a drug that’s been accelerated through to approval and there’s no confirmatory trial coming through for eight, nine, or 10 years, and then that trial comes through and is negative, then what happens there? That’s an interesting discussion, from both a philosophical and a financial standpoint, about who bears the risk for that. Those are some of the pieces of work we want to get into, thinking about what the incentive process is around that. Ross, I know you have one or two examples as well where drugs have been around for a while and have gone through the accelerated process, but still don’t have a confirmatory outcome at the end of the day.

Dr. Maclean: Yes, thank you, Mike. Dr. Mouabbi, I wanted to pick up on one interesting point you made. As a practicing oncologist, you had used bevacizumab and had found it to be a helpful adjunct in the care of your patients, only to be disappointed when some of the indications were found not to have efficacy and safety. I think it exemplifies one of the great tensions in medicine, which is the perspective of an individual patient, or in your case, an individual provider.

This is oftentimes very anecdotal based upon very small numbers, whereas the population health scientist or the regulator also looks at it from a population perspective, meaning a bigger N (number of patients). It would be a very unusual physician who is going to be capturing data on all of his or her patients over the course of many years so that he or she can generate aggregate data on whether a drug has efficacy in a real-world setting. I think you’re exemplifying a tension between what individuals remember and the ability to aggregate that over the course of many years or many patients, which is clearly a very difficult thing to do.

Second, to pick up on Mike’s point about value for money and the cost to the federal government, we also have aducanumab from Biogen for Alzheimer’s disease as a great example. This drug, despite significant debate and controversy, received accelerated approval and then arrived on the market with what many might call a high price. Now, we could spend all day debating price versus value, but at the end of the day, this was a high price. If you’re the federal government, you were potentially facing huge costs to provide this treatment to so many people who had signs of cognitive impairment.

There have also been these poster children that have pushed the boundaries of what accelerated approval was originally intended for. Mike’s comment about rare, uncommon, high-unmet-need conditions where there’s really no treatment option is quite different from accelerated approval for a drug that might potentially treat millions or tens of millions of people with a chronic ailment. I think sometimes the industry can bring challenge upon itself by pursuing accelerated approval for drugs for common chronic illnesses.

Dr. Mouabbi: Definitely. We’ll get into that in a second, but I’m really curious, do you know a percentage of how many accelerated approvals eventually make it to a full approval?

Mr. Glover: It’s about 50%.

Dr. Mouabbi: That’s a problem, right?

Mr. Glover: That’s the problem. If you think about the Alzheimer’s example, I know it’s outside of oncology, but that was a drug that was going to take a minimum of 10 years to show an outcome. This was agreed between the FDA and the organization that launched it. It was going to take 10 years to show some outcomes. That’s an example of Ross’s question, “Is the accelerated approval process fit for purpose when it’s going to take 10-plus years to get an outcome?” I think that could be where there are potential misalignments and incentives between pharma and the FDA.

We are seeing other examples of drugs that have accelerated approval in the US but aren’t launched elsewhere. They don’t get regulatory approval in the European space because of the data sets they come to the market with. I think there are other discussions to have about, “Okay, what exactly does accelerated approval mean for us in terms of the data set we are going to have, and how quickly will we get confirmatory outcomes”? In your space, the major outcome is overall survival (OS). What does that look like for a particular drug? Do you get OS in one year or are you going to get it in 10 years? What does it look like to really drive that forward? That’s why I think that some of the misalignment and the decision between what the accelerated approval is and what the outcomes could be are from a physician’s perspective.

Dr. Mouabbi: That’s an excellent segue to my next question. How does the availability of accelerated approval influence biopharma in term of innovation? Specifically in the oncology section, but we can talk about other sectors as well—more specifically, if we can dive into the pricing strategy, because you’re right. Whenever an accelerated approval comes, the price tag is pretty hefty. How does it also influence the drug development? If I’m a pharma company and I’m developing a drug and I can go for an accelerated approval, I’m going to be aiming for that first, because it can be a source of huge revenue as we’re waiting for more data from another study to confirm it. How do those factors influence biopharma?

Mr. Glover: It’s a great question. It’s very easy to tip into a cynical perspective here when you talk about this type of approach for accelerated approval. Once you launch your product on the market, the clock starts in terms of the lifecycle of the brand when it’s out in the marketplace. If you are waiting for your confirmatory trials three, four, or five years later when you could have had four or five years on the market and accelerated approval generating those high revenues and high costs, there’s actually a bit of a perverse incentive to drive towards accelerated approval and get it out there quickly.

Now, one of the discussions we should be having in this space is how do you get the FDA and pharma companies to talk about what alignment in incentives looks like? You could say, “Well, I’m going to get my accelerated approval now and I’m going to kick the can down the road in terms of what outcomes and overall survival look like in the confirmatory trial.” Now, I don’t think pharma do that, and I’ve been involved in that discussion, but it’s easy to see how that could be part of the discussion about, “Well, actually, if we can wait three or four years for the confirmatory trial, that’s three or four years we’ve been on the market.”

I think that’s where there’s a discussion for the FDA to be clear on, “Okay, we’re going to launch, and we’ve got two years to get data. Let’s start to think about what interim OS should look like so we know we’re on the right track.” There are some discussions that we should be having between pharma and the FDA, but what does the incentive process look like to have products on the market? Well, you have physicians and patients saying, “I want access to this drug.” You now have the right to try, which is kicking around in the background as well. There are patients who have no other options to go for, and they can ask a company to supply a drug. That’s the final step in terms of getting patients onto potential outcomes in exploratory medicine, but I do think in this space where the accelerated approval process is in place, there should be a much more robust discussion between the pharma company and the FDA about the milestones put in place to make sure we’re actually seeing this drug do what it’s supposed to do.

Dr. Maclean: I’ll add just a couple of points to build off Mike’s comments. Going back to the end point debate, I think what accelerated approvals have shown is that the FDA and the manufacturer should also be debating which end point is appropriate. It’s very easy to say, “Well, it should all be about overall survival,” but that has huge implications on the duration, viability, and size of trials, and therefore the costs. At the same time, if we go for surrogates such as response rate or progression-free survival in the case of cancer, this potentially makes the trials much faster. That then raises all the risks and the concerns about surrogates.

We just completed and published some research on progression-free survival, which highlights something really important that I think we’ve all heard before. It’s attributed to Abraham Lincoln, but I think we’ve all heard it from our elders and betters, which is, “Value the life in your years, not the years in your life.” The research we just completed shows that in several different cancers, given the choice of overall or progression-free survival as an end point, many patients would naturally pick overall survival. But a significant number of patients differed and said, “Well, life is not infinite. I’m more interested in having a meaningful response, but having a high quality of life with that. Of the days that I’ve got life, I want to make them high-quality.”

I think it triggers an interesting debate. OS as an end point has its challenges and therefore makes accelerated approval very difficult, and other surrogates are imperfect. Well, what’s the happy medium where we get end points that matter to the patient and matter to the provider, but aren’t necessarily the hardest of all end points, which is just pure survival? I think it raises an interesting debate.

The second comment is we are seeing emerging technologies that are potentially going to transform this. Tokenization is something we’re beginning to hear a lot about, which is the ability to, in a Health Insurance and Portability Accountability Act (HIPAA)–compliant way, link the data of a patient in the United States from across different settings. For example, Dr. Mouabbi, it would be possible to link a patient in a clinical trial to their data post-trial when they go back to the clinic, are cared for by their insurer, and live their life. This potentially offers a technological solution that might allow the innovator, the biopharma company, to follow these patients and generate the overall survival data, but without the huge logistical constraints of long-term extensions, as Mike said, of five- or 10-year-long trials.

I think there are emerging solutions which may also mean that there’s a path forward, but it’s only going to happen if the FDA and the innovators are all speaking to each other.

Mr. Glover: I’ll pick up on the end points piece, because I think it’s a really important point to think about, particularly from two perspectives. First, what is a physician trying to achieve in terms of that medicine and that therapeutic area? What does the patient want to achieve? As you say, the patients want that quality of life whilst they’re still surviving the disease. OS may not be the overall goal, depending on what happens with the disease and moving towards end-of-life care.

There is a discussion here, particularly in a disease area where there are very few options. Obviously, this is where accelerated approval starts to really show itself in terms of the options available. Just what will the patient’s quality of life look like, and what types of end points do you need to think about? That, again, is a rich source of discussion to have between the pharma, the innovator company, the FDA, and the physician and patient population. What does it look like to have those discussions going on? I think it’s important to think about that.

Then in terms of the end points themselves, is PFS what you want to drive for, and how long do you need to do that? Thinking about a single-arm environment where you have a very rare area with only one or two products in that space, it’s very difficult to put comparatives in place. How you we best collect real-world evidence to demonstrate that you have an outcome and that you’re being beneficial to that patient population? I think that is a very underexplored area, not just in the US, but globally, where the regulatory authorities may not look as robustly what real-world evidence can give to help drive an outcome in the accelerated approval space. Those are a few areas to really dig into in which pharma and the FDA and innovator companies can really start talking more closely about.

Dr. Mouabbi: I fully agree. As a treating physician, I can tell you that what my patients really care about is to stay on a drug for as long as possible and to have as much time as possible for disease control. When we talk about overall survival, I tend to explain to them that it’s not with this line of therapy, it’s overall. How much can all of their lines of therapy improve their survival? When I talk to them like this, it can be challenging for them to hear. They want to know that this line of therapy is going to work and it’s going to work for a long time for them.

We can go through the weeds of that a little bit. Is achieving full FDA approval the primary goal of a study? I can give you an example for that in the breast space, when we talk about cyclin-dependent kinase (CDK)4/6 inhibitors. All of the studies that looked at them had a primary end point of progression-free survival. If you look at all the different drugs we have across all the studies, their hazard ratios are almost similar, around 0.5 across the board. Overall survival was not a primary end point; it was a secondary end point. None of those studies were really powered to capture it, but it was a secondary end point that they were looking for. They found that one drug did meet the overall survival end point, whereas the other two did not.

Now, there’s a big debate in the field whether or not we should follow the one that had overall survival and drop the other two. What do you say for that? Should a study’s approval come because of its primary end point, or should they look for other end points like overall survival? If so, should overall survival be a primary endpoint in those studies?

Dr. Maclean: Good question. I’m going to plead the fifth on that. I’m not sure I’m qualified to render an opinion on a mandate that, in the case of cancer trials, the primary end point should be the only end point. I think that would potentially be too narrow a view and would not give patients those options. At the end of the day, for some of these treatments we’re looking at people who are very sick, coming towards the end of their life regardless of the treatment options. For them, this is a very difficult benefit-risk discussion in what remains of their life. Going back to our opening comments, I hear you loud and clear on the multiple different statistics and end points and data points, but I think we have to also find that balance between safe, efficacious medicines and giving patients the hope that something is out there that might help them.

Mr. Glover: I think the key phrase you said there is “benefit-risk discussion,” and that’s a benefit-risk discussion between the innovator organization, the FDA, the physician, and the patient. This is particularly important in an area where there is a high unmet need, such as a disease where there are very few options and you’re coming first or second to market, or in a very rare disease where there are no other options available. I think that discussion needs to be, “Okay, well, what end points are really important for us? What end points are going to show that the patient is benefiting and the risk-benefit ratio is going the right way?” It may not be OS—it may be PFS, it could be response rate, it could be something else, or it could be mixture of all of those points coming together.

I think what’s important to understand is that the physician, the patient, the FDA, and the innovator company go into the discussion with their eyes open about what the benefit is going to be for the population you’re serving. That’s why there is a mixture of end points. I wouldn’t, from my perspective, want to mandate that we need to have OS or that’s the end of the game. I want to have a discussion about just what is important for the physician and the patient to achieve in their treatment options. Is it PFS, is it a mixture of PFS and response rate, or is it something else? That’s a discussion I think you need to have with the physician and the patient together.

Dr. Mouabbi: That’s excellent. Now, to the fourth part of this meeting, let’s look ahead. How do you envision the future of FDA accelerated approvals in oncology? Are there some new emerging trends that we can use? I like the one that you mentioned, the tokenization. Can you define it again and talk about how it might fit in the future, where we can capture in real life the survival of the patient after they come off the study?

Dr. Maclean: My perspective is that the future of accelerated approvals offers a huge opportunity for pharma to further advance transparency and to own it when drugs appear not to work. Everything we have discussed and that you’ve raised, Dr. Mouabbi, around choosing endpoints, what matters to patients—the fact that this could be transparent and in the public domain, published and debated, is clearly very important. Even more important than that is that when a signal appears that a drug does not work, the company should own taking that off the market as quickly as possible, but should also own removing the drug for use in that indication in an active manner. This should also be done in countries beyond the FDA’s remit, because this is a global issue around lack of efficacy and potentially a safety concern.

There’s a famous statement that a drug that doesn’t work is nothing other than a safety concern, because the patient’s likely going to get none of the efficacy and some of the side effects. I think there’s a chance for the pharmaceutical industry to take leadership there. There’s also a chance for the regulator to be viewed to partner appropriately in evolving what accelerated approval actually looks like in the 2020s. Mike?

Mr. Glover: I couldn’t agree more. I think the ownership piece is an important discussion where the individual organization needs to step in and have an honest discussion internally. What does it look like when a drug has a signal to show that the intended outcome isn’t the right outcome or isn’t going the right way? That is an open discussion between the innovator organization and the FDA. This comes back to what the right incentives are to have a drug go through the Accelerated Approval process, so that when you do get those signals that things aren’t going the way they should be, the incentives are in place to take action and remove the indication if needed.

I agree, Ross, that this discussion should not just be for the country where the accelerated approval is, but in any country where you have the indication launched. If that signal is going the wrong way, then that’s a signal to say that the drug should not be used in that area. It comes back to the discussion about what incentives look like in 2025 and 2026 onwards. I think there is an onus on the pharma organizations and the innovative companies to engage the FDA through the Pharmaceutical Research and Manufactures of America (PhRMA) or through other sources and say, “How do we align or realign what incentives look like in the accelerated approval process?”

The recent Alzheimer’s discussion was addressed to see Biogen withdraw one of the drugs recently. It’s going to accelerate the discussion about what an aligned incentive program looks like for accelerated approval drugs. I think that’s an important discussion that should be kicked off and accelerated by the pharma organizations to say, “We need to have a discussion with you, FDA, and with the physician population about what the right incentives are to make sure that both we and the patients themselves are benefiting from new drugs being on the market.” I think that’s the next step in this discussion.

Dr. Mouabbi: This is all very excellent. I learned a lot about this topic. It’s very interesting to hear about the questions that are emerging around it. It has definitely offered much more clarity today. Before I end, do you have any closing remarks, anything you’d like to add? I’ll start with you, Mike, and then go to Ross.

Mr. Glover: I think one of the interesting points for the patient, the physician, and the FDA—particularly if you’re a patient and there are no other options—is that the accelerated approval process allows a patient to get access to a drug that they may not have had access to before in an earlier space, in an earlier phase of their disease, or in a phase of their disease where they need something that they can’t get access to. I think the accelerated approval process is an important process. It’s an important process for patient outcomes, physician outcomes, and for the population as a whole.

For me, moving forward, I need to see more interaction between the innovator organization and the FDA about exactly what we are trying to incentivize here. Are we incentivizing earlier access? Are we incentivizing profit motivations for pharma companies? I think that’s an important discussion we need to get into to ensure that the outcomes are the right outcomes, and it’s a mix of outcomes that are beneficial for the whole population.

Dr. Maclean: Thank you, Mike. I have one very brief comment to build off Mike’s use of the term “profit maximization.” There is a moment of leadership for the pharma industry. In the chance that a drug that was being approved under the accelerated approval process is ultimately found to work, congratulations, continue with the commercialization and safe and appropriate use of that. Well done, you’ve played by the rules. Let patients and prescribers have access to it. But if it hasn’t shown to work, let’s own that and get that drug or indication appropriately off the market and no longer used. I could imagine a scenario where some of the stakeholders who paid for that drug, which was ultimately found to not actually work or potentially cause harm, wondering where the revenues went that they paid for that patient. I think this is a chance for pharma to own that before something is imposed upon them.

Dr. Mouabbi: Definitely. With that, I want to thank both our guests today, Ross McLean and Michael Glover, for this very, very interesting interview. To our audience, thank you so much for joining in, and I look forward to the next one. Thank you so much, and have a great day.

About the Speakers

Jason Mouabbi, MD, is in Assistant Professor in the Department of General Oncology and the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, where he specializes in lobular breast cancers. His research focuses on the management of breast cancer subtypes and their impact on treatment.

Ross Maclean, MD, is the Executive Vice President of Precision Health Economics & Outcomes Research and the Head of Medical Affairs at Precision Value & Health. In this role, he is responsible for medical support for health policy, economic research, and business development. He has more than 20 years of experience in health services and outcomes research, health system design, and health economics.

Michael Glover is a Partner at Qinexa Consultancy, LLC, a company which designs and delivers high-quality professional development for pharmaceutical and nonprofit organizations. He has decades of experience in global market access, asset delivery, and policy and pricing strategies across oncology, metabolic, cardiovascular, and neurosciences therapeutic areas.

For More Information

US Food & Drug Administration (2023). Accelerated approval program. Available at: https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program

MacEwan JP, Doctor J, Mulligan K, et al (2019). The value of progression-free survival in metastatic breast cancer: results from a survey of patients and providers. MDM Policy Pract, 4(1):2381468319855386. DOI:10.1177/2381468319855386

MacEwan JP, Gupte-Singh K, Zhao LM & Reckamp KL (2020). Non–small cell lung cancer patient preferences for first-line treatment: a discrete choice experiment. MDM Policy Pract, 5(1):2381468320922208. DOI:10.1177/2381468320922208

Transcript edited for clarity. Any views expressed above are the speakers’ own and do not necessarily reflect those of Oncology Data Advisor. 

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