There has been a lot of ink spilled, and bytes spent this week discussing the FDA’s approval of aducanumab, brand-name Aduhelm, for the treatment of Alzheimer’s Disease. I have mixed feelings; there are advantages to a Phase 4 study, but how do you say no to hope?
What we know – providing context
Alzheimer’s Disease (AD) is a devastating illness that robs one of their “self” long before the end of life. In addition to the tragedy to the patient, it has enormous financial and psychological costs to their families and our health systems. In 2017, about 2 million Medicare beneficiaries, and it is the over-65s where AD is predominant, used one of the available drugs for AD – they constitute the future audience or market for Aduhelm. The FDA’s approval used a regulatory pathway for:
“a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.” [emphasis added] FDA press release
The presence of amyloid deposits is the surrogate endpoint, but their role in AD remains unknown; are they a cause or an effect? We know that the “amyloid hypothesis” has not yielded any clinical benefit until now. Two Phase III trials, EMERGE and ENGAGE, funded by Biogen yielded ambiguous results, one showing cognitive improvement, the other not; both demonstrated that Aduhelm was relatively safe. The FDA has the data, but it has not been widely published in medical journals. I found one from Alzheimer’s and Dementia that suggested another Phase III trial. It is based on a slide deck prepared for Biogen’s investors, so it meets SEC guidelines, but is not peer-reviewed. You can read it for yourself here.
Despite a decidedly negative evaluation by the experts empaneled by the FDA, it was approved with only a few important caveats. Patients must have documented amyloid disease, demonstrated by either a Positron Emission Tomography (PET)  scan or a sampling of the fluid in the central nervous system by a spinal tap. They must be monitored for the primary adverse reactions Amyloid Related Imaging Associated (ARIA) brain swelling (edema) or bleeding (hemorrhage) by MRI studies along with two MRI studies done at weeks 7 and 12 of treatment. Finally, Biogen must collect information that constitutes a Phase IV post-marketing study.
Phase IV studies
Even after a drug’s approval, adverse responses and, in some cases, outcomes are followed. Much of that data is maintained by different physician groups with a vested interest in the efficacy of the treatment they provide and recommend. As a once-practicing physician, I think that Phase IV studies are vital. Real-world effectiveness can be far different than a tightly controlled Phase III study. Outcomes and safety may be far different when the prescriber is insufficiently trained or experienced in the use of a drug or procedure.
If Aduhelm’s phase IV registry, it is after all just a collection of real-world results, shows heightened safety concerns or diminished efficacy, the FDA will withdraw approval. With a financial windfall possible for Biogen, some have suggested that it may take quite some time to get the registry up and running. A reader of Derek Lowe’s excellent In the Pipeline blog suggested that in following the science, Biogen would tightly restrict eligibility, utilize academic centers where patient recruitment is slow, and openly compete with the registry by marketing the use of the drug to patients; all resulting in an incomplete study at the end of the nine years the FDA has given Biogen to show real-world efficacy. An incomplete investigation would then need to be extended while Biogen is collecting $56,000 a year per patient for treatment. You see, the cost of this Phase IV study is not on Biogen; it is on us, more specifically patients and insurance companies, especially the insurer of first and last resort, Medicare.
Aduhelm, a drug given by infusion, is covered on Part B of Medicare, with care provided by a physician. In this instance, care will be most often given in an infusion center. Under current payment protocols, physicians receive 6% of the cost of the drug for providing the infusion services, roughly $3400 annually. For patients, there will be an out-of-pocket cost of about $11,000, subject to their coverage. The payments and co-pays will be different if the payor is a health insurer other than Medicare.
While Medicare will pay for the use of any FDA-approved drug that is “reasonable and necessary,” private health insurance will undoubtedly require additional documentation before agreeing to the treatment – rationing care by “hassle.” Medicare may also make a National Coverage Decision that restricts patient access based upon specific criteria. That might make good sense because the equivocal results for Aduhelm are limited to those with mild AD; it has no efficacy for moderate or severe disease.
In any instance, those patients receiving Aduhelm will still require that initial PET scan or lumbar puncture, and those two MRIs all costs passed on to them. Medicare currently pays about $80 for an invasive lumbar puncture and about $4000 for a non-invasive PET scan. Which would you choose?
And, unlike a Phase III study, Biogen is not picking up any of this tab. But while these downstream costs are easily quantified, they pale in comparison to the psychological costs to patients and physicians
“Our fear all along was that there was going to be a steep decline in all of my mental faculties, but to date, that has not been the case,” he says. “I’ve had some symptomatic issues . . . but the medication really is about more time, more time with my loved ones, those are critical things.” An AD Patient
For a devastating disease without a cure, Aduhelm is a godsend of hope, an emotional response that is not to be taken lightly. Ask a patient being treated for cancer. In fact, many of the costly medications used to treat late stages of cancer only extend life by a few months; there is precedent for the FDA approval in that sense.
Patients and families will be pushing very hard to get this drug, and they are not going to be objective when it comes to determining its value; maybe Dad has a few better days a month and can recognize you and chat for a few minutes. Is that $56,000 worth of efficacy, irrespective of who picks up the tab?
Who will say no to starting or stopping therapy?
While it may be the payor's decision, the message will be delivered by the primary care physicians. They will once again be made “gatekeepers,” a role that had previously in the early days of health maintenance organizations (HMOs). It was a horrible job then, and it will be so now. How can you deny a patient or family hope when that is all there is to give?
Much of the media coverage of the FDA’s decision on Aduhelm has focused on its financial costs or benefits and the inexact science upon which that decision was predicated. But for me, the actual costs are about cost-shifting. Biogen has a way to continue studying the possible efficacy of this drug on the taxpayer’s and patients' dime while enhancing their revenue. More importantly, the job of taking away hope has been shifted onto our primary care physicians, and it will produce additional psychic stress for them and their patients, further tearing at the fabric of the doctor-patient relationship.
This decision also lowers the bar on what the FDA will approve. The reported results for Aduhelm are perhaps, maybe, a bit better than those of a dietary supplement. Is it fair to say that at this threshold for efficacy, the FDA could just as well have approved hydroxychloroquine for treating COVID-19?
 A PET scan is similar to a CT scan in that slices are obtained across our body, but in this instance, the “dye” used to provide contrast is a radioactive chemical that can identify underlying cell activity.
Sources: VoxCare The new Alzheimer’s drug could break Medicare