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Tuesday, June 8, 2021

Aducanumab, Brand Name Aduhelm, Will Cost $56,000 in the U.S., Plus More for Testing

 (Edited for better clarity, PS added.)

... and they're touting it as "affordable" - *snort*

I guess when you're charging $100,000 to $500,000 for cancer monoclonal antibodies, it's a sweet deal, maybe lol -  but those drugs have proven efficacy.

Aduhelm does not have proven efficacy - or at least there are questions about its efficacy, with many prescribers actually refusing to prescribe it.  

I mean, would you buy a $56,000 car and not even be sure it will ever start?

"Oh, but the longer you have the car in your garage, it MIGHT start, because lab tests showed it started in 1 out of 250 tries over time? "

What the ...? LOL!

In car world, we'd say ...

"Erm - no. Considering there are known problems, I'm not giving you $56,000 upfront for this car.  I'll agree to a lease for $2,333  a month under a two-year contract, and if it doesn't work, I get to give it back, the contract ends, and I get a refund, minus administrative fees." 

So in pharma world, why can't it go like this?

"Yeah, no - how about I give you a $10,000 installment payment contract of good faith for the drug alone, we pay for testing and IV infusion.  If the drug works within two years - meaning there are no new amyloid plaques AND no lower-average decline in 6 MMSE scores - AND there are no grade 3 to 4 adverse events - we pay you the other $46,000.  

"Either that or we pay you $56,000 upfront and if there are amyloid plaques, a lower average from 6 MMSE scores, or grade 3/4 adverse events in a two-year contract, you refund us entirely."


"So now, you have 3 choices, Biogen. You can ..."


(1)  "Either lower the price or give deep discounts/rebates to us as commercial insurance and Medicare -  PLUS - significant copay assistance to our commercial patients AND income-scaled price reduction for our uninsured, underinsured, and Medicare patients (because Medicare patients don't qualify for copay assistance under current federal law). 


- OR - 

(2)   "Take one of the two value-based agreements/lease offerings detailed above." 


- OR - 


(3)   Though we, as a commercial insurance company or Medicare may eventually be legally required to put it on our formulary, since there isn't anything else for Alzheimer's -  DO realize that we can and will put so many step-through edits and prior-authorization restrictions on it that it'll never be approved, because no one will ever ever be able to jump through all the hoops (which we MIGHT do anyway, considering the iffy efficacy and safety) - and you can kiss our collective arses and nice doing business with you - your call."

LOL!  Ah, if only we could. 

Actually we can and have done formulary exclusions or medical-exception exclusion, but no one ever does value-based agreements/leases, because when they've tried, pharma says, "Oh, can you prove the patient was adherent to the drug and took it as prescribed?"

See, they gotcha - if it's an oral drug or self-administered injection, no medical professional was at home with the patient, making sure they took it regularly - it's pharma's out-clause of value-based contracts.

But actually, with this one, we could prove patient adherence because it's infused at a clinic, administered by healthcare professionals :)

Plus the average length of time a company stays with one particular insurance company plan is two years - so they've paid all of this money upfront for lifelong treatment, only to watch the patient's employer switch to a cheaper plan in two years, who hasn't and won't pay a dime for the drug. 

Also, keep in mind that already-overburdened Medicare will bear the brunt because these are senior patients - meaning we, the taxpayers, will be paying $56,000 PER PATIENT for a drug that we're not even sure works - PLUS - the cost of the study trial-design requirements, which are MRIs, EEGs, PET scans, and administering the MMSE at regular intervals - which costs an additional $20,000 to $60,000 per year.

However, like I said in my first and original post on this subject, we have nothing else, so I get approving it, unless there are safety concerns - and apparently there are safety concerns as well?  

You are certainly welcome visit clinicaltrials.gov for the results of the EMERGE, ENGAGE, and EMBARK trials on aducanumab, but the results aren't posted yet.

The best you can find are analyses in peer-reviewed journals - though I don't believe the premier reviewer for neurology treatments, the AAN (American Academy of Neurology) has published anything yet?

Here's a link to an excellent analysis from a world-renowned peer-reviewed medical journal, The Lancet, regarding the concerns. 

Otherwise, here's my simplified synopsis, if I've read and  understood all of the different analyses correctly ...

Biogen first did two studies in 2015-2019, EMERGE and ENGAGE, with ENGAGE being a longer trial and with dosing differences  -  both of which failed to show statistical significance versus placebo, and were thus halted in 2019.  

Then after re-opening the study in 2020, and being granted a 3-month extension by the FDA in March of 2021, Biogen did an EMBARK post-hoc analysis study,  where Biogen was allowed to add new data, and claimed that actually, the slight improvement between the two trials was statistically significant, and showed even greater improvement at a longer interval with dosing changes.

HOWEVER -  some of the problems are, in Cliff Notes version lol:

1)  There were more people studied in ENGAGE than EMERGE, and yet despite slight improvement between the two (after Biogen was allowed to add more data with EMBARK), neither's outcomes were considered to show  enough statistically significant change by usual FDA standards.


2)  The placebo arm of ENGAGE declined more rapidly in EMERGE which is cause for concern, because these are people not on treatment.   This typically means something is wrong in the study design that needs to be ferreted out before continuing trials - why such a variability  of decline in placebo, non-treated patients?  


This is an indication that either the control arm was NOT controlled or that, more likely, we don't understand enough about the progression of Alzheimer's in general to explain rapid decline in non-treated patients.


3)  Considering the varying levels of decline in placebo, it raised questions about ability to determine not just the true efficacy of aducanumab, but the true safety as well - especially considering Biogen's assertion that longer time on the drug results in better efficacy - but we don't know yet about the safety longer term because not enough time has passed yet.


4)  "Decline" is defined either as new amyloid plaques on MRI or exhibiting cognitive decline on the MMSE (Mini Mental Status Exam, neuropsychological testing), or both - and therein lies the problem.   Because though patients may not have new amyloid plaques, they can still show rapid decline on the MMSE for unknown reasons.


So what if you show no new amyloid plaques, but you have a significant a decline on the MMSE cognitive testing - does that mean the drug works?  Does it mean it doesn't work? 

Well, it depends on the primary endpoint of the study.  

If the primary endpoint is only to reduce formation of new amyloid plaque growth -  then it sometimes works. 

If the primary endpoint is to slow mental status decline in Alzheimer's patients - which is what Biogen's press claim says - then no.

The problem is, we don't understand yet why a person can rapidly decline in mental status without having any new amyloid plaques or new growth of old ones - and yet it happens regularly -  which makes you wonder if stopping growth of new amyloid plaques even matters in slowing the progression of Alzheimer's, and it's not the old plaques  (or something else) causing the decline?  

Because it is still possible we've misunderstood, and that the amyloid plaques are actually just another symptom of Alzheimer's, rather than its cause? 


Plus, people with Alzheimer's have good days and bad days.  Just like an visual-acuity eye exam, your results on the MMSE can vary on good days or bad days - so an average of several MMSEs given at intervals over time, rather than one test, is best to prove efficacy of a drug.



5)    The FDA inexplicably broke its own rules for this drug repeatedly, beginning in 2019,  giving extra time x2, and almost appearing to collaborate with Biogen rather than review it, for reasons unknown. 
In other words, fill in the blank here with whatever possibilities your mind comes up with, keeping in mind, we have no proof, just speculation, and that it's likely multifactorial combination, i.e., pressure for treatment, economy-boosting, recouping losses after COVID? 


Erm record scratch on that last one - only the company and shareholders would profit and benefit, because as already stated,  already overburdened Medicare and the taxpayers will pay the brunt of the cost for this drug, which hasn't proven efficacy, so who's really benefitting, other than Biogen and its shareholders?


Out of everything I've read,  I think this opinion piece from Bloomberg does a much better job than I did of giving the best brief synopsis of the culmination of concerns I've read by peer-reviewed medical journals, physicians, and insurance companies, both commercial and public.  

"Follow the science" has been a consistent refrain during the pandemic, and it's usually a core mandate of the Food and Drug Administration in evaluating medicines. But when it came to one of the agency's most consequential decisions — the approval Monday of Biogen Inc.'s controversial Alzheimer's drug aducanumab — science took a back seat.

Alzheimer's is a devastating illness with no treatments that do anything but ease symptoms. Biogen's drug is the first said to slow decline. If there was good evidence that it did so, it'd be a breakthrough, but the data is inconclusive at best. And while the FDA is and should be flexible when patients have no options, this decision does more than bend standards — it shatters them.

For Biogen investors, the approval is a huge victory, setting the stage for a blockbuster drug worth billions in sales and added market value for the company; already, after an initial halt the stock surged 50% on Monday’s news. For everyone else, it’s a mistake; the FDA’s blessing threatens to harm the agency's reputation, America's health budget and the quality of drug research, including for Alzheimer’s.

Here’s the issue: Biogen started two identical studies in 2015 to test whether the drug slowed early Alzheimer's. However, the company halted them in March 2019 after an early analysis suggested a low chance of success. It was the presumptive end for the medicine until Biogen popped up a few months later with the shocking announcement that one of the two trials showed a benefit — once it added new data — and that it planned to file for approval.

The early halt was problematic. Biogen collected a fraction of the patient data it wanted, introducing statistical uncertainty. But the biggest issue is that the second study failed, and it wasn't close. The FDA's desired standard for approval in Alzheimer's is evidence from two positive studies. There are good reasons to want a high bar and duplication. It's much harder to objectively measure mental decline than the size of a tumor, making definitive evidence especially critical.

The FDA ducked this standard by giving the drug a so-called accelerated approval, using a regulatory pathway that lets the agency accept different types of evidence in areas where patients lack options. That doesn't make the decision more defensible. In this case, the approval centers on aducanumab’s ability to remove amyloid brain plaques believed to play a role in Alzheimer's. Biogen's drug (which it will market under the brand name Aduhelm at a hefty price of about $56,000 a year) cuts plaque, but the resulting patient benefit in even the positive trial is so modest that it may not be significant.

Many other medicines have targeted amyloid. Unfortunately, all failed to help patients, leading scientists to question whether removing the plaque does anything. Biogen's opposing results only add to the uncertainty about the role of amyloid; they don't make it acceptable as the basis for a multibillion-dollar approval. What is certain is that removing the plaque causes sometimes serious side effects, including brain swelling.

Biogen has explanations for the failed trial, blaming insufficient dosing and a few rapidly declining patients. But, unfortunately, this is what's known as post-hoc analysis, or less politely cherry-picking, and it is fundamentally and irrevocably biased. Good scientists use such methods to generate ideas for future tests, not as tentpoles for generationally significant drug approvals.

You'd expect the FDA to push back. But, in this case, a part of the agency not only shifted its standards but collaborated with Biogen through an approval process in which it was so cozy with Biogen that consumer advocacy group Public Citizen has asked the government to investigate. That’s even as an independent panel of experts convened by the FDA to evaluate the drug universally advised against approval in November. Moreover, the regulator's own statistical expert was highly critical of the evidence presented in a briefing packet presented as part of the November review. And on June 2, the American Geriatrics Society, a group of health professionals dedicated to older adults, wrote directly to the FDA's interim commissioner advising against approval.

The FDA seems to have yielded to the pressure to give hope to patients, even if it may be false, despite the consequences. And there are many. If the agency approves drugs with middling evidence, that's what it will get. Companies will be more likely to seek approval or advance programs based on weak results, wasting time and research dollars and the health of patients who participate in clinical trials. As for Alzheimer’s, future drugs may be badly delayed. With an approved treatment available, it will likely become harder to recruit people to participate in trials. And now that the FDA has validated amyloid as a target, companies may focus on it at the expense of other potentially more fruitful avenues.

The price of the drug is just the beginning of the financial damage. Getting it will require doctor’s visits and scans to establish eligibility and monitor side effects, creating significant additional costs for Medicare, patients and their caregivers. Multiply those costs by even a fraction of the millions of Americans with Alzheimer's, and you have a budget crisis.


PS ... 

Allow me to add one further concern not mentioned in any of the three posts yet, but is actually likely the most obvious problem  - if the FDA bent the efficacy and safety rules for this drug, what problems is that going to cause for other pharma drugs with high prices and iffy efficacy/safety?

Also, I didn't mean to make insurance companies sound the hero above - they can be, and help mitigate costs -  but let us not forget that they're still for-profit corporations - which means if they can find a way to place more out-of-pocket cost to the member rather than themselves, they will.

For example, i.e. read about the new site-of-care mandate restrictions and "white-bagging" policies being instituted for certain drugs in my last post on this subject on Monday. 

These site-of-care, specialty-pharmacy, and "white-bagging" policies which save the middle-man cost to insurance companies, but do little to nothing for the administration costs to the providers and the clinics, nor to out-of-pocket costs to the patients - which is who those costs will ultimately fall upon - not to mention problems with product tracking, product integrity, etc. with white-bagging.

Now, insurance companies claim any cost savings for them is cost savings for us - but we have yet to ever once see those savings "trickle down" on us lol - our premiums just continue to go up and up!


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