The TITANIC defense and ADUHELM

Crushed

I am not a neuroscientist I have no personal knowledge of  whether Aduhelm works.  But I have studied Science based safety regulation  in particular the FDA since the early 1970s.

ADUHELM backers, including the Alzheimer's Association are using the TITANIC argument that it was  "approved" by government regulators.  In this case the FDA. 
My answer, based on a career of studying regulators and regulations is SO WHAT?

You have to look at the entire regulatory approval process not the fact of approval. 

Ill use the TITANIC  lifeboat approval as an example.  The Titanic was allowed  to sail with lifeboats for a third of the people on board based on an "surrogate approval"  that Bulkheads and wireless would mean rescue ships could come quickly enough that lifeboats for all were not needed .    However the regulators did nothing to ensure  that this rescue system would work
1) The radio operators were "contracted out" and had no obligation for safety 
2)  Ships had no obligation to keep a current track of their position
3)  No system existed to ensure that rescue ships were nearby
4) no lifeboat drill s were required to make sure that passengers could be loaded safely in the boats. 
ETC ETC ETC

The regulatory approval was worthless in terms of life safety  

Aduhelm is no different.  The regulatory approval was not based on any  proof that it "works" in any detectable clinical way.  The surrogate endpoints were not presented to advisory committee or the scientific community for comment for their predictive quality.

The regulatory approval as such is worthless in terms of proving benefit to patients  

Shame on the Alzheimer's Association  leadership

   

The European Medicines Agency noted that although Aduhelm reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established. Results from the main studies were conflicting and did not show overall that Aduhelm was effective at treating adults with early stage Alzheimer’s disease.

In addition, the studies did not show that the medicine was sufficiently safe as images from brain scans of some patients showed abnormalities suggestive of swelling or bleeding, which could potentially cause harm. Furthermore, it is not clear that the abnormalities can be properly monitored and managed in clinical practice.

Therefore, the Agency’s opinion was that the benefits of Aduhelm did not outweigh its risks and it recommended refusing marketing authorisation.

  
 
 

Michael Ellenbogen

While we lost the battle we have not lost the war. The next step may crush CMS if we chose to go down the next step. I wish you would stop focusing on this one drug because there is a much bigger picture to this that you do not seem to understand. And by the way I do have at least 10 top scientist that do believe in this.

MN Chickadee

From everything I have read it seems it should not have been FDA approved in the first place, and certainly CMS was reasonable in its decision to not spend more than $30,000 per year per patient on it. Participants in one of the clinical trials only had slight improvement, the participants in the other had no benefit. 40% had brain swelling. The safety risks of this treatment have been under examined and glossed over. The FDA reportedly worked way more closely with this pharmaceutical company, Biogen, than is typical in a normal review prompting investigations by congress and numerous oversight committees that are underway. Meanwhile the Alzheimer's Association received $1.6 million from pharmaceutical companies in one year including a half a million from Biogen. Why, oh why, would these biotech companies be donating so much to the AA? To be nice? No, not how they work. More likely for the expectation of cooperation in situations like these. I want to have hope for a successful treatment as much as anyone, but it's become clear it's not this and the regulatory process of this one has been corrupted, and has also sullied my view of the AA.

Crushed

Michael Ellenbogen wrote:

While we lost the battle we have not lost the war. The next step may crush CMS if we chose to go down the next step. I wish you would stop focusing on this one drug because there is a much bigger picture to this that you do not seem to understand. And by the way I do have at least 10 top scientist that do believe in this.

 Here is what AA writes

The Centers for Medicare & Medicaid Services (CMS) issued a draft decision that essentially denies coverage of treatments targeting amyloid for Alzheimer’s disease, including aducanumab (Aduhelm™), the first FDA-approved therapy to address the underlying biology of Alzheimer’s disease. The proposal deals a serious blow to everyone with dementia

Sorry the Alzheimer's association is doubling down on this drug and regulatory c approach
"targeting amyloid" means no proof of clinical effectiveness

Are you describing scientists who believe in the amyloid hypothesis or scientist who think the drug shows meaningful effectiveness ?  

They are not the same

• Perspective
• Published: 17 February 2022

The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

• Eric Karran &
• Bart De Strooper

Nature Reviews Drug Discoveryvolume 21, pages 306–318 (2022)Cite this artic  

• Metrics details  

 

 

Abstract

Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD — Aβ plaques and tau neurofibrillary tangles — and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.
 
That is as good as it gets right now It is a researchable idea that might work and is worthy of a proper clinical trial 

  

  
 
 

 

Michael Ellenbogen

This is not just about what AA thinks. There are many others invoved in this fight.

toolbeltexpert

Crushed

Michael Ellenbogen wrote:

This is not just about what AA thinks. There are many others invoved in this fight.

Im only interested in those with no financial links to similar drugs

I know why they hat the CMS

Medicare has laid a path for other companies to understand where the bar for coverage is set: A drug must be safe and offer a meaningful benefit to patients, and it must do so over time. This is good news for Eli Lilly & Co. and Roche, both of which have Alzheimer’s therapies that will soon be up for approval.

That is why they depend on politics to get this drug approved without proof 
 

  

 
 The furious debate over Biogen’s Alzheimer’s treatment has now sparked controversy at the Alliance for Aging Research, an advocacy group that has seen half of its scientific advisory board members resign after learning the organization had lobbied against a Medicare proposal to restrict coverage of the medication   STAT

 the Neurology Center in Washington, D.C., which has gone so far as to ban Biogen employees from entering their seven office locations in response to the controversy shrouding the company’s new med.“Biogen representatives should not enter or engage staff, physicians or patients,” according to an image of one of the clinic’s signs posted to Twitter, which Fierce Pharma has confirmed with the center.
 
 

Michael Ellenbogen

I have to say folks as it seems many do not understand the damage this had done to the dementia field. From top leaders and scientist and neurologist they all feel we went back 10 years in time in this filed by the actions taken. I heard from so many that are now progressing faster because they don’t have access to the drug. So I agree this is the Titanic of dementia and we are sinking on all the progress made in the last 10 years.  

 

Lane Simonian

I have a much more optimistic view of Medicare's decision.  Aduhelm should never been approved by the FDA in the first place.  It did not help those without the APOE4 gene at all.  It may have provided a clinically significant slowing down of the disease in a few people with two copies of the gene but with the risk of brain swelling and brain bleeds.  

Medicare did backtrack a little bit in that it might approve future anti-amyloid drugs if they actually show efficacy.  The one drug in this group that produces similar results to Aduhelm but that does not produce serious side effects is ALZ-801.

The scientists and Alzheimer organization leaders that cling to the amyloid hypothesis refuse to relinquish the reins.  There is always an answer to failed trials: the drug was not given early enough, it was not given in a high enough dose, it did not target the right form of amyloid, it did not remove enough amyloid.  Amyloid, though, is only a secondary trigger for the disease and then only in APOE4 carriers.

What has set the treatment of Alzheimer's disease behind by a decade is the control of the discussion of the disease by those who support the amyloid hypothesis of Alzheimer's disease.  To quote the scientific philospher Karl Popper:

“Whenever a theory appears to you as the only possible one, take this as a sign that you have neither understood the theory nor the problem which it was intended to solve.”

• Karl Popper

Maybe other hypotheses for the disease will now be able to see the light of day.

Crushed

Michael Ellenbogen wrote:

I have to say folks as it seems many do not understand the damage this had done to the dementia field. From top leaders and scientist and neurologist they all feel we went back 10 years in time in this filed by the actions taken. I heard from so many that are now progressing faster because they don’t have access to the drug. So I agree this is the Titanic of dementia and we are sinking on all the progress made in the last 10 years.  

 

 I understand

  

 A whole lot of people with their hands in the taxpayers pocket are real upset that they might have to show that a drug actually works  They thought the FIX was in with a golden river from surrogate biomarkers No progress was made. That is why they have no evidence of clinical effectiveness

The approval of Aduhelm risks eroding public trust in Alzheimer research and the FDA
Jason Karlawish &

• Joshua D. Grill

Nature Reviews Neurologyvolume 17, pages 523–524 (2021)Cite this article  

The FDA has granted accelerated approval to aducanumab (Aduhelm) for the treatment of Alzheimer disease with an overly broad label. The decision disregarded key aspects of scientific process and risks eroding public trust in research, regulatory science and the FDA.

  

  

Michael Ellenbogen

That guy is a jerk as I know him and Penn is the worst places for clinical trials. My only friend that I liked there just died and he would disagree with those folks. And he was at the top of all of them.

Michael Ellenbogen

This guy was one of the best and we lost agreat one. We worked on many things together. He was so smart and willing to hear what others said unlike the idoit above. 

John Trojanowski

sandwichone123

Hear here, Lane! What we need is *clinical* success.

Crushed

Ive been an expert witness and have analyzed and taught scientific and medical expert evidence for many years. One Federal judge called me an expert on experts  

 One of the minor advantages of legal proceedings is you get to cross examine the  experts and determine the basis for and limits of their expertise.  Far too often medical experts use what  the law calls    IPSE DIXIT  

 

 

"Ipse dixit is a Latin phrase that translates to “I say it is so myself ”

 

  What the law does is require an expert to prove that field of expertise actually knows what it clams to know.    You may be a Grand Master of the Society of Witch Burners with thirty years experience is identifying witches and having them burned, bu that does not prove that witches exist.  

This is what the whole debate on Aduhelm is about.  
NO ONE KNOWS IF LIMITING  OR ELIMINATING  AMYLOID HAS ANY CLINICAL EFFECT

It is still a gigantic experiment What the FDA APPROVAL flag wavers seem to ignore is that the FDA approved it as hardship experimental drug based on surrogate endpoints
In other it called FDA approval but its not the same as routine or even and emergency FDA approval.  It is approval based on guesswork 
 

  

  
 
  

 
"The debate over the amyloid hypothesis has now moved from the lab to the clinic, as the era of amyloid plaque–removing agents for AD is upon us. Whether this will be the first step toward successful treatment and perhaps prevention of AD, or an expensive setback to the field, remains to be seen"
 

Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside

 

Erik S. Musiek, … , Teresa Gomez-Isla, David M. Holtzman

Published October 15, 2021
Citation Information: J Clin Invest. 2021

https://www.jci.org/articles/view/154889/cite