Is Accelerated Approval Successful?

 I know that title is a little click-baity, but I couldn't come up with something short that really captured the complexity of this issue.

The Journal of the American Medical Association published a study last week that looked at treatments that were given Accelerated Approval in the last 10 years. It's called "Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval." The question they sought to answer (and this is quoted from the article) was "What is the clinical benefit of cancer drugs granted accelerated approval, and on what basis are they converted to regular approval?" In other words, how successful are cancer drugs that are given accelerated approval?

A little background, just so we're clear on what all of this means and why its important. The issue has been on my mind a lot lately, as a couple of posts that I wrote last month would indicate.

Most treatments that get approval from the FDA use the results of a phase 3 clinical trial to provide data for the application. Phase 1 trials are usually very small, and their main purpose is to show safety -- they help determine the best dose of the treatment to be effective while being safe. Phase 2 trials focus more on effectiveness, and use a larger number of patients to show that the treatment actually works. Phase 3 trials are, ideally, randomized and double-blind, meaning the new treatment is given to half of the patients in the trial, while the other half gets the old treatment (the "standard of care" -- the one that patients would usually receive). This allows for a direct comparison between the new and the old, so the FDA can see that the new is more effective and/or safer than the old. 

With accelerated approval, the makers of a treatment can apply to have their treatment approved after the phase 2 trial. Accelerated approval is usually given for treatment classes that are brand new, allowing a potentially life-saving treatment to get to patients faster then if they went through the full trial process. This benefits patients because a treatment might get to them sooner. And it certainly benefits the maker of the treatment because they can start making money (and recouping the money they put into research) sooner. 

But part of the deal is that the clinical trial process has to continue. A "confirmatory trial" has to happen to show that the good results from the smaller phase 2 trial will actually hold up over time. If the trial is successful, then the treatment gets full approval. If not, then the treatment is withdrawn.

The JAMA article, then, wants to know just how successful those accelerated approvals are -- how many actually go on to get full approval.

The authors looked back at the 129 cancer treatments that were given accelerated approval by the FDA between 2013 and 2017, and then looked at the 46 of them that had follow-up data after 5 years. The results were not great, in terms of how many showed an improvement in survival or quality of life -- only 20 of the 46 (or 43%).

Despite that, 29 of the 46 (63%) went on to get full approval. Another 10 (22%) were withdrawn, and 7 of the (15%) were still in the confirmatory trial process.

Looking at those 29 that did get full approval, only 7 of them (24%) were shown to improve both overall survival and quality of life. Another 7 improved overall survival but not quality of life, and 6 improved quality of life but not overall survival. The remaining 9 did not improve either one.

Those number are very important, which is why I'm sharing them, but I also have to point out some limitations here. I'm not able to access the full article, so I'm not sure how they measuring "quality of life." Overall survival is easy enough to measure, but quality of life is harder, and I'm not sure every study uses the kinds of patient-reported quality of life measurements that I'm familiar with. I guess that's how they measure safety, looking at the side effects that patients experienced? That would be the standard measurement in a clinical trial. If that;s the case, I really do not like referring to it as "quality of life." That completely ignores a whole lot of things that should be included in a measurement of the quality of life. 

Aside from that, Overall Survival is a complicated measurement, too. There are certainly cancers that are so aggressive that new treatments are successful when they add months to a patient's life. Then there are others, like Follicular Lymphoma, that have OS measured in years. The measurement can be so long that the median OS hasn't been reached in 5 years. That's actually very common in FL treatment trials, which is why they use Progression Free Survival as a measurement instead. So without looking at the full article, I can't tell if they are counting something like that as improving OS or not improving OS.

This is what I meant when I said it was all kind of complex.

Ultimately, though, I'm not sure those details matter.

The authors of the study provide this conclusion: "Most cancer drugs granted accelerated approval did not demonstrate benefit in overall survival or quality of life within 5 years of accelerated approval. Patients should be clearly informed about the cancer drugs that use the accelerated approval pathway and do not end up showing benefits in patient-centered clinical outcomes."

I would hope that any conversation about treatment with an oncologist would include that information, and that any oncologist would take that into consideration before recommending it to a patient. But I also know, based on the kind of enthusiasm that lots of oncologists had for PI3K inhibitors, that they aren't going to wait for full approval before using them, and that even a preliminary OK from the FDA is good enough. And probably should be.

So, I'll ask the question again that I ask in my title -- Is Accelerated Approval Successful? 

By some measures, No, it isn't. If more than half of accelerated approvals don't result in a better experience for patients, then it seems like the system failed. On the other hand, if the goal is to get new improvements to patients more quickly, than it's a success. And if a large number don't get full approval, then that IS a success. Arguably, the system works -- the treatments that aren't doing the job don't last. If the FDA gave them early approval and then just forgot about them, that would be a problem. But the follow-up makes sure that they are as god as the smaller trial showed.

Of course, "success" isn't just about how well the system works. It's about the patients who get the treatments. Every confirmatory trial that failed means a bunch of patients who didn't get the treatment they had hoped for. And that hurts to think about. From what I can tell, a lot of the treatments get accelerated approval because they offer something that available, standard-of-care treatments can't offer. Think about something like a bi-specific. It works on cancer cells in ways that no other treatment works. If the confirmatory trial involves mostly patients who have tried everything else they could, and they have hope for this new thing that might work in a different way, then that's a success. Clinical trials are necessary, and trials need participants. 

It's all so complex. 

In the end, I think Accelerated Approval has its place, and the authors are right -- being fully informed is key to it all. Talk to your oncologist about treatments, about clinical trials, and about anything else that concerns you. (But you knew that already, you smart, informed FL patients....)