The Problems with Accelerated Approvals

I've been doing a lot of reading lately about the FDA approval process and some of the things that make it problematic. There have been a couple of really interesting books published in the last year that look at this process from a couple of different angles. I may try to write about them soon. But the big theme that I find in all of my reading is that the when new treatments are up for approval, there is a delicate balance that needs to be achieved -- the safety of the treatment and its effectiveness for patients, the desire for doctors to help their patients but also to keep them safe, the need for drug companies to make a profit to justify doing research, etc. It's a very complex process.

So it was interesting to see an article in JAMA Internal Medicine a couple of weeks ago that highlighted some of these issues in ways that are similar to the books I have been reading. 

The article is called "Clinical Trials Portfolio and Regulatory History of Idelalisib in Indolent Non-Hodgkin Lymphoma."

Now, I will admit to a small obsession with Idelalisib and other PI3K inhibitors. It was about a year ago that they were pulled from the market, or voluntarily withdrawn. I wrote about this a few weeks ago. The problems came because of safety issues (more serious side effects, including patient deaths, than were expected). There were also problems with recruiting enough patients into the trials, probably because of the Covid pandemic (but also, I think, because there were at least 4 PI3K inhibitors competing for the same patients).

PI3K inhibitors fascinate me because they held so much promise (and maybe still do?), and got oncologists very excited about their possibilities. Their trial results were very good, and they worked against cancer in new ways that targeted the cancer cells while sparing many healthy cells (unlike the way chemotherapy works). 

As I've written before, several PI3K inhibitors (including Idelalisib) were given accelerated approval by the FDA. This meant that the companies could start selling the treatments, and doctors could start prescribing it, based on the results of small phase 2 clinical trials. The stipulation was that a larger phase 3 trial would be conducted to confirm the small phase 2 trial. The term "accelerated approval" is probably not completely accurate. It's more like "temporary approval." It allows the manufacturer to start earning some money on the treatment earlier than usual.

Here's the problem, as the JAMA article points out -- the issues with serious side effects were already clear, up to 6 years before the withdrawal from the market. The researchers who wrote the article looked the clinical trials involving Idelalisib. There were 31 of them. 20 of those involved indolent lymphoma (including Follicular Lymphoma). During the period after the accelerated approval, the results of 6 of those trials were available. These 6 trials were Randomized Clinical Trials, meaning they allowed a direct comparison between Idelalisib and another treatment. And in those trials, it was clear that Idelalisib had higher rates of serious side effects and patient deaths than the treatment it was being compared to.

The big problem here? It was six years later that Idealisib was withdrawn from the market, and in those 6 years, the manufacturer had $842 million in sales (though they declined over time, as problems became evident).

It's a tricky thing. Patients need new and better treatments, and businesses need incentive to spend money to develop them. Accelerated Approval from the FDA seemed to solve both problems -- promising treatments get to patients sooner, and businesses begin to make money sooner.

But, as the article's authors point out, there needs to be greater oversight during the process. It's not enough to complete the phase 3 trial and then ask for approval; there need to be steps along to way to make sure things are doing well, particularly in terms of patient safety. There isn't much incentive for a company to make trial results public after Accelerated Approval. That needs to change.

I hear lots of patient opinions about drug companies, and the kind of gray area we are all in. We need them, but we don't trust them -- I think that sums up a lot of our attitudes. Problems like this doesn't make us trust them any more, but it certainly makes us need them more.

My biggest fear with a situation like this is that it damages patient trust in other ways -- in the clinical trial process itself. If we are being asked to be a part of a trial, but problems are being "hidden," will that make fewer people want to be a part of them?

I hope that's not the case. I hope that anyone interested in a trial places their trust in the oncologist who they are working with -- someone who can explain the potential risks as well as the benefits, and pay close attention to each individual patient to make sure they are staying safe. (In the books I read about this process, that was very clear -- the oncologists working directly with patients made it a priority to protect those patients. They were kind of the heroes of the stories, even if they were in the background sometimes.)

And I hope none of you are turned off from being a part of a trial. They're the only way we find new treatments, as risky as they are, by their nature. 

Cancer is a complex thing -- within our bodies and outside of them. But like knowing all I can about my disease, I'd still rather learn about the process and know what I'm dealing with than be in the dark.