The FDA's decision to greenlight the Alzheimer's drug Aduhelm was controversial. Still, it wasn't a complete surprise to those of us who have witnessed head-scratching approvals for oncology drugs.
You can't put the toothpaste back in the tube. Can't un-ring that bell. Can't put the genie back in the bottle.
The difficulty of undoing decisions has weighed on my mind lately, as I've pondered the state of accelerated drug approvals in the United States. It seems that once a drug gets its foot in the door, it's nearly impossible to shut it out, even if the drug proves ineffective.
Since 1992, the FDA has granted "fast track" approval for drugs that address an unmet need and show promising initial results—typically on surrogate measures such as tumor shrinkage. This approval comes with a stipulation: Afterwards, the drug maker needs to conduct studies to confirm that its therapy extends overall survival, improves quality of life, or both. If those studies find no advantages for these most important endpoints, the FDA could remove approval.
Yet, that rarely happens. Among oncology drugs, only 10 of 155 accelerated approvals have been withdrawn from the market or are in the process of being withdrawn. That's due in part to the lack of follow-through on post-approval studies promised to the FDA. According to one 2017 analysis, just 54% of these studies were completed five to six years after the commitment was made. Another 20% were never started.
These statistics should be concerning to anyone who has followed the Aduhelm saga. The first new Alzheimer's drug to hit the market in 20 years, Aduhelm received fast-track approval from the FDA in June, although an advisory committee voted almost unanimously against it. In clinical trials, the drug had not performed better than a placebo at delaying progression of Alzheimer's, and it carries significant toxicities. Aduhelm was approved based on evidence that it reduces buildup of amyloid brain plaques, a marker of Alzheimer’s, yet the hypothesis that these plaques cause the disease has been losing credence.
If we do see benefits from Aduhelm, they are likely to be modest—months instead of years of delayed progression—and won't be immediately obvious. For that reason, the FDA gave the drug makers nine years on the market to produce evidence confirming that this $56,000-a-year drug works. Even with a recent revision to the FDA label that narrows Aduhelm's indications, the Medicare program could spend tens of billions of dollars before we have answers.
Part of a Pattern
As an oncologist who tracks FDA approvals for a living, I was as baffled by the Aduhelm decision as many other observers. Yet, it felt more like a recurring nightmare than a wake-up call. While Aduhelm may be one of the more extreme examples of questionable drug approval decisions, oncology is rife with drugs that are approved based on thin evidence, then linger on the market for years without proving a clear benefit to patients.
The difficulty of removing an indication for an entrenched drug became clear in late April, when the FDA's Oncologic Drugs Advisory Committee (ODAC) met to review data surrounding six indications for three immunologic cancer drugs. For all indications, post-approval studies had failed to clearly demonstrate the hoped-for results. In the meantime, some of these drugs no longer address an unmet need; new drugs have been approved for that indication after demonstrating meaningful results.
From New Century Health's perspective, there was a strong case that most of the approvals should be revoked. We had previously made the decision not to include four of these indications on our high-value clinical oncology pathways. Yet, the ODAC's recommendations went the opposite way, suggesting that the FDA keep approval for four of the six indications, pending further studies into their efficacy. The FDA has yet to act on these recommendations.
I've heard a range of perspectives on ODAC's votes. Some oncologists have been flabbergasted by decisions that they see as driven by frustration and desperation when treating terrible forms of cancer. They see it as a betrayal of the agreement that allows fast-track approvals to be made. Dr. Vinay Prasad, an oncologist and high-profile critic of the FDA's track record on cancer drugs, wrote on Twitter, "If the FDA keeps these drugs on the market, we have a big problem. The social contract of accelerated approval is violated. Companies will learn a powerful lesson: Never voluntarily withdraw. ALWAYS FIGHT."
I've also listened to the arguments on the other side. As I heard ODAC members explain on several occasions, they are reluctant to give up treatment options for patients who have terrible forms of cancer for which there is no game-changing therapy. Also, while drugs may not improve care on a population level, there are subgroups of patients who do benefit from the drugs. (Unfortunately, it's still very hard to predict who those patients will be.)
Thinking Big to Change the System
I've come to side with the critics. Unless the FDA enforces its agreements with drug-makers, they will have little incentive to conduct rigorous post-approval studies. When those studies are presented, they will fight like crazy to keep the indication, knowing that the FDA will likely give them the benefit of the doubt. It's not hard to imagine a similar scenario playing out with Aduhelm when—and if—the evidence is available at the end of this decade.
What can be done to fix this situation? Could the National Institutes of Health, National Cancer Institute or another respected third party carry out the studies—on the pharma companies' dime—instead of the companies themselves? This would dramatically increase the chances that promised studies are completed. Second, what if we could somehow put limits on how much drug makers can charge for therapies that receive accelerated approvals? Imagine if they could only receive an amount equal to the cost of the current standard of care, or some percentage thereof, until they receive full approval. Financial incentives would compel the companies to either wait until they had enough data to make a strong case for standard approval, or quickly conduct the required follow-up studies after achieving accelerated approval.
I admit these might be pie-in-the-sky ideas. There are many others we might consider. But recent events have convinced me that we need systemic change—a true breakthrough cure for what ails the drug-approval process.
A Tough Position for Providers and Health Plans
When a drug of dubious value gets fast-track approval, the responsibility of sorting out effective drugs from ineffective ones flows downhill to providers and health plans. In a world where patients are desperate for cures and cancer drugs are featured in Super Bowl commercials, it's not an enviable position. Patients clamoring for hope against Alzheimer's or cancer may insist on a drug, even if its benefits are a long shot, and modest at best.
While strong action from the federal government would be optimal, plans and providers have some options. High-value clinical pathways, such as those we maintain at New Century Health, are one defense against use of ineffective drugs. By keeping low-value therapies off pathway, plans can disincentive their use. Well-designed alternative payment models that reward providers for following the evidence can help counteract the perverse incentives of traditional fee-for-service medicine, which rewards providers for prescribing more expensive drugs. Keeping unproven drugs off hospital and health plan formularies can also send a powerful message.
As disappointed as I have been in recent drug-approval decisions, the eternal optimist in me hopes that this will be a watershed moment. The Aduhelm approval brought together many of the most troubling aspects of our fast-track process into one high-profile example for the world to behold. Congressional committees have launched probes into the FDA and drug maker about the approval process, as well as the price tag. Three members of the FDA advisory committee resigned in protest.
And while the ODAC decisions are lower in profile, the fact that it reviewed drugs in the first place hopefully marks the start of an era of greater government scrutiny.
Over the years, the accelerated approvals program has paved the way for many lifesaving and life-improving treatments to reach patients before all the evidence is in. The wild success of our COVID-19 vaccines is an undeniable example, and we have many others within oncology. However, lowering the threshold for expedited approvals threatens to undermine the entire program.
Let's hope that the FDA and elected officials recognize the moment we are in and fix the process. We can still reverse course.
About the AuthorFollow on Linkedin More Content by Andrew Hertler, MD, FACP