Proposed Legislation Could Put Expiration Date on Accelerated Approvals

New legislation has been introduced to the House of Representatives that could potentially codify the FDA’s authority to require post-marketing studies on cancer therapies that have received accelerated approvals and potentially limit how long they can stay on the market without additional data. Likewise, this decision could have a significant negative impact on patients with cancer currently undergoing treatment with therapeutics that have received accelerated approval.

Representative Frank Pallone (D-NJ), chairman of the House Energy and Commerce Committee, proposed the Accelerated Approval Integrity Act or H.R.6963, which would place a 5-year limit on how long drugs can stay on the market without confirmation of clinical benefit or notable progress. According to Maurie Markman, MD, the proposal came as a result of patient deaths from a non-oncologic drug designed to treat Alzheimer’s disease that received accelerated approval despite its limited benefit and high price tag.

“I hope [clinicians in the oncology space] understand the potential danger here. Individual oncologists can do relatively little, but organizations like the [American Society of Clinical Oncology] and American Cancer Society, certainly can make this point loud and clear with congress,” Markman said.

In an interview with CancerNetwork®, Markman, president of Medicine & Science at the Cancer Treatment Centers of America, spoke about the reasoning behind the legislation, how it might impact patients within the oncology space, and what other solutions may exist.

Could you expand on the role clinical benefit plays in this proposed legislation?

There are those who say that clinical benefit in oncology is only defined when a drug in a phase 3 randomized trial—or perhaps even 2 phase 3 randomized trials—has been shown to result in a statistically significant improvement in overall survival [OS]. Anything short of that is a surrogate end point, which is not clearly clinical benefit. If you want to approve a drug on that basis, you have to go back and do a study that shows an improvement in OS.

Cancer is increasingly a chronic illness. As a result, when patients finish treatment on a randomized trial today, at least in the United States, patients are allowed to receive subsequent therapies that may impact their outcome. We have so many drugs and so many diseases now that impact outcome. Once a patient completes therapy on a phase 3 trial with progression-free survival [PFS] as the primary end point, they may get 1, 2, 3, 5, or 10 different [subsequent] therapies, all of which may impact their outcome. They may be able receive a study drug after they’ve progressed on a [prior drug], making OS that you might measure years later incredibly difficult, if not impossible, to [measure].

The FDA understands this because they are increasingly and appropriately proving therapies on the basis of PFS as a primary end point. Sometimes even high objective response rates [are used] when the patient population is small because that’s what molecular medicine is all about. We’re now seeing populations that are 10%, 5%, 2%, or 1% of an individual tumor type based on the molecular markers. [Based on] molecular findings for that patient, if you were to do a phase 2 randomized trial, it may take 10, 15, or 20 years to finish. Of course, that will never happen. The FDA said, this is not necessary. Although we might prefer it, the reality is that it will not happen.

Why do you find this development concerning?

If a law is going to require [that] you approve a drug based on PFS or high response rates in a very rare subtype, but you then have to do a phase 3 randomized trial and get it done within 5 years to report an improvement in OS or [they will] pull the drug off the market, this will be disaster. I cannot overstate this. I’m concerned about it.

[There’s another] point about this, and I don’t know that I’ve actually ever seen this point highlighted in a publication. But if the FDA were to say to a company, ‘You’ve got to do a phase 3 randomized trial, and you’ve got to get done in certain period of time,’ where is the discussion about whether patients would be willing to participate in such a study? Why should a patient participate in a study that is of no benefit to them just because the FDA says it needs to be done?

I’m very concerned if something goes into place, [and a given trial] doesn’t meet that timeline, the FDA can’t do anything about it and the drug is pulled from the market. How many patients may die as a result of that? A rhetorical question, but one that’s deadly serious.

Is there a better solution than what has been proposed?

[In] the FDA’s current iteration, the laws [that were] put into place are now more than 60 years old, [and] there has been very little change. We’re talking about cancer 50 to 60 years ago—it’s very different today. The idea is that if you had an anticancer therapy 60 or 50 years ago, and you said this drug has got to show improvement in OS, you got answers pretty quickly. One of the reasons we got answers very quickly was because the outcomes were so poor.

But we’ve now moved to a totally different dimension. If that sounds out of place, perhaps that’s where we need to be. We now have effective therapies; we have therapies that go beyond individual tumor types [that are] based on molecular targets. We have therapies that look at individual subsets of tumors that might be 1%, 2%, or 3% [of the population].

What I think [clinicians], the FDA, and regulatory bodies need to do is to come up with better nomenclature. If the word or the term accelerated approval that we use in oncology is the same term, expression, and category of approval as the drug for Alzheimer’s disease, then that has got to be changed; they get lumped together. We are talking about something that should have never seen the light of day and we are talking about the lives of tens, hundreds, or thousands of patients [with cancer who] will be affected by this.

If you delay the time [for] a patient with cancer to develop symptoms [and they are] able to have a good quality of life defined by them, not by a statistician, but if the patient finds it is meaningful then that’s valuable. That’s clinical benefit.

If you accept the argument that these therapies are improving survival but you can’t show them in a phase 3 trial, we have to recognize that as being a fact. We have used PFS as an end point, not as a surrogate end point, [but as] a primary end point because you can’t go beyond that. Now, I’m not saying you couldn’t show in a phase 3 randomized trial that a new drug in cancer improves OS. I’m simply saying that if you don’t, you cannot conclude it doesn’t improve OS. It may very well be that everybody benefits from it.

[Its] like the experience with using imatinib [Gleevec] in chronic myeloid leukemia [CML]. Imatinib changed the world of CML, but it has never been shown in a phase 3 randomized trial in the frontline setting to improve OS, even though patients now live 10, 15, or 20 years. Why? Because in the trial where it was compared to interferon α, patients were crossed over to imatinib when they progressed. At the end of the day, there wasn’t an improvement in OS even though there was a massive improvement in PFS. Does that mean that imatinib didn’t improve OS? Of course, it does, but just not within that trial.

We need a rethinking of the terminology. Maybe we need to pull oncology out of the accelerator approval framework and call it something else, so it doesn’t get lumped in with such horrible processes as were used with the Alzheimer’s disease drug.

Reference

Legislation would set expiration for FDA’s accelerated approvals. News release. Regulatory Affairs Professionals Society. March 9, 2022. March 15, 2022. https://bit.ly/3q6BFeE