About Controversial Approval of Biogen's Alzheimer Drug

Two weeks ago, the US Food and Drug Administration (FDA) approved aducanumab (brand name Aduhelm) as a treatment for Alzheimer's disease -- a historic decision not because it addresses the longstanding unmet medical need for a safe and effective cure of a devastating disease that affects nearly 6 million Americans, but because of the unprecedented irregularities of the agency's actions, undermining its mission to protect public health and ensure the "safety, efficacy, and security" of treatments made available in the United States. 

The winner is obviously the drug developer, Biogen and its collaborator Eisai. They probably never thought that FDA would be so collaborative and more desired to approve aducanumab than the sponsors themselves. They rescued a drug that had been declared 'unlikely' to work (futility) just two years ago. They got an unlimited label for all Alzheimer patients (beyond the early Alzheimer patients that were studied in their clinical trials). They can decide on the drug price whatever they want because there is no price control in the US once the drug is approved by the US FDA. They have at least 9 years to complete the post-marketing confirmatory study. There are no incentives for them to complete this confirmatory study as early as possible. The longer the study takes, the more time they can make the money from a drug with unproven efficacy. 

The losers include a long list: 

• FDA - loses its credibility
• Alzheimer's patients - are given false hope and may end up taking 'snake oil' for many years down the road
• Patient Advocacy Group - Alzheimer's Association was unhappy with Biogen's $56,000/year/patient price tag. 
• Medicare/Medicaid/Insurance Companies - extremely high cost associated with Aduhelm ($56,000/year/patient) and the broad label for Aduhelm can cost them a lot of money
• FDA Adcom Committee - insulted by FDA's decision to approve even though the Adcom voted overwhelmingly against the approval
• Regulatory science - FDA has touted for years about the regulatory science and the strict rules to be followed for drug approval - these rules are not followed by the FDA - what can you do?
• FDA statisticians - It is clear that the FDA statistical reviewers had their dissenting opinions and questioned the data / results from two pivotal studies that were prematurely discontinued due to futility. Statisticians' opinions were overruled. 

......

Usually, approval like this will be heralded as historical and celebrated by all parties - not this time for aducanumab approval. The reactions are overwhelmingly negative. Here is a list of articles discussing the controversial approval from different angles.  

• Aducanumab Approved to Treat Alzheimer’s Disease
• Editor's Corner—The FDA's decision on aducanumab will drag down innovation for years to come
• FDA's 'intellectually insulting' aducanumab decision opens up a regulatory foothold for leading competitors
• New Alzheimer’s Drug Heightens Debate Over FDA Accelerated Approval Process
• The F.D.A.’s Extraordinary Approval of a Questionable Treatment for Alzheimer’s
• 6 ways the FDA’s approval of Aduhelm does more harm than good
• Biogen Alzheimer’s drug approval was 'surprising for a lot of people': Eli Lilly CEO
• The FDA Is Failing the American People
• New Alzheimer's drug sets dangerous precedent
• How the new Alzheimer’s drug works—and why the FDA is under fire for approving it
• Pharma industry insiders disavow FDA's approval of Aduhelm
• New Alzheimer's drug approval fallout: Public Citizen seeks removal of FDA's Woodcock, Cavazzoni and Dunn
• Controversial drug approval stokes concern about lack of a permanent FDA chief
• Key senator calls for Woodcock's removal as FDA fallout from Biogen Alzheimer's approval heats up
• Aduhelm Approval Raises Concerns About US FDA Leadership, Senate Finance Chair Suggests
• Biogen says FDA didn't push for trial before Alzheimer's approval
• Biogen's $56K price on Aduhelm 'simply unacceptable,' Alzheimer's Association says after vouching for FDA approval
• AdComm member quits over FDA approval of Biogen's Aduhelm
• AdComm exodus: 2nd expert quits over FDA approval of Biogen's Aduhelm
• Third member of FDA expert committee resigns over controversial Alzheimer’s therapy decision
• Why a controversial decision won’t stop me from serving on FDA advisory committees
• Aduhelm Approval Firestorm Raises Question: What Are US FDA Advisory Committees For, Anyway?
• Opinion: The FDA is in desperate need of some soul-searching
• The approval of aducanumab isn’t the end of the story. It’s just the beginning
• New FDA documents show internal dissent on Aduhelm approval
• What controversy? Eli Lilly plots Alzheimer's BLA filing later this year as FDA taps more anti-amyloid drugs as breakthroughs
• ALZHEIMER'S DISEASE: Open the Floodgates
• New York Times: A New Alzheimer’s Drug Offers More Questions Than Answers
• New York Times: How Aduhelm, an Unproven Alzheimer’s Drug, Got Approved - The New York Times (nytimes.com)
• How cozy is too cozy? FDA and Biogen offer up a test case – Endpoints News (endpts.com)
• We’re seeing what happens when the FDA loses credibility
• ICER: FDA Has Failed In Its Responsibility To Protect Patients From Harm
• Aducanumab Glass Half Empty. No, It's Half Full | MedPage Today
• CNN: The road to Aduhelm: What one ex-FDA adviser called 'probably the worst drug approval decision in recent US history' for an Alzheimer's treatment

In approving Biogen's aducanumab, the boundaries between the FDA (as a regulator) and the sponsor (as a drug developer) were crossed. In the drug development field, the sponsor will try everything to exaggerate the benefit and minimize the side effects while FDA will need to be on the conservative side, tamper down the expectations, prevent the manipulation of the data and biases in data analyses,...  In the aducanumab case, FDA is determined to approving the drug no matter what and no matter whether the data/ results from clinical trials have demonstrated "Substantial Evidence of Effectiveness". FDA retrospectively find a regulatory pathway (accelerated approval pathway) for approval. In doing so, FDA failed to stand by the standards it established and both regulators and sponsors had followed.

In the drug development field, pre-specification is critical. The regulatory pathway, the number of clinical trials for clinical development program, the clinical trial design, study endpoints, and statistical analysis plan have to be discussed and agreed upon with FDA. As Eli Lilly's CEO said that in drug development, "where the gold standard for approval is you call your shot, and then you hit your shot, like Babe Ruth pointing at the left-field and then hitting his home run there." The sub-group analyses and post-hoc analyses are for hypothesis-generating and can not be used to support the regulatory approval. In Biogen's case, it is obvious that an additional clinical trial is needed before the approval. By switching to the accelerated approval pathway, FDA essentially agreed that the pivotal studies with cognitive and function measures provided insufficient evidence for approval and they had to retrofit to find accelerated approval that is based on the biomarker (amyloid).

In a letter from FDA to AdCom about switching to the accelerated approval pathway, Dr. Billy Dunn said this: 

Following the advisory committee meeting, further discussion within FDA considered the uncertainty introduced by the conflicting results of Study 302 and Study 301 and the committee’s discussion of that uncertainty. Our discussions raised further consideration of the accelerated approval pathway; a topic discussed earlier in the development program but not directly discussed during the advisory committee meeting given the focus at that meeting on the evidence of clinical benefit. As you may be aware, the accelerated approval pathway is for drugs to treat serious diseases that are expected to provide a meaningful advantage over available therapy, but where there is residual uncertainty regarding the drug’s ultimate clinical benefit. To be approved under this pathway, there must be substantial evidence of the drug’s effectiveness on a surrogate endpoint—usually an endpoint that reflects the underlying disease pathology (accelerated approval can also use an intermediate clinical endpoint). An effect on this surrogate endpoint must be shown to be reasonably likely to predict clinical benefit. We concluded that these requirements were met for aducanumab, with substantial evidence that the drug reduces amyloid beta plaque, and that this reduction is reasonably likely to predict clinical benefit. For drugs approved using the accelerated approval pathway, further study is required to verify anticipated clinical benefits

FDA is preoccupied and determined to approve aducanumab no matter which pathway is used. The following conclusion is subjective and a lot of people will certainly not agree: "We concluded that these requirements were met for aducanumab, with substantial evidence that the drug reduces amyloid-beta plaque, and that this reduction is reasonably likely to predict clinical benefit." Had the FDA been so sure about the biomarker 'amyloid-beta plaque' reduction is 'reasonably likely to predict clinical benefit', they would advise the sponsors (Biogen and other Alzheimer drug developers) to design their phase III studies with the primary efficacy endpoint being the lowering the amyloid-beta plaque, not the measuring the benefit in improving the cognitive and function. 

Accelerated approval pathway is described in FDA guidance for industry "Expedited Programs for Serious Conditions – Drugs and Biologics", but is only used in a situation where the confirmatory studies with clinical endpoints have not been conducted. In Biogen's case, two confirmatory studies with clinical endpoints had already been completed (actually was stopped early for futility). It is a round peg in a square hole to retrospectively going back to the accelerated approval pathway based on the biomarker because of the conflicting and unconvincing results from confirmatory trials with clinical endpoints. Approval of aducanumab based on an accelerated approval pathway breaks agency precedent. "Accelerated approval is traditionally used for treatments that haven't yet proved themselves in large trials. In Biogen's case, Aduhelm went through two Phase 3 studies and came up with conflicting evidence."

FDA also loses its fairness - there are a lot of diseases with unmet medical needs. The drugs for other unmet medical conditional have been tested and generated stronger evidence than Biogen's pivotal studies, but the drugs were rejected by FDA. Here is an article about ALS (amyotrophic lateral sclerosis) - more deadly than Alzheimer's disease.

FDA's controversial Aduhelm decision leaves ALS patients feeling spurned

The FDA's controversial approval of Biogen's Aduhelm drug for Alzheimer's disease has been met with fierce resistance from all corners of the biopharma industry, but few seem to be as upset with the decision as ALS patients and advocacy groups.

For all that's already been written and discussed about the agency's announcement, from the drug's exorbitantly high price of $56,000 per year to criticism over lowered standards, ALS patients see something more. ALS patients and associations say they largely regarded Aduhelm's approval as a bittersweet double standard: happy that those with Alzheimer's have a new drug available, but questioning how the FDA evaluated Biogen's drug compared to the experimental programs being studies for their own disease. 

Nothing punctuated the feeling harder than the agency's announcement in April that a promising drug under development by the biotech Amylyx would need another study to confirm efficacy. This program, called AMX0035, hit the primary endpoint for improving function specifically laid out in the FDA's 2019 guidelines for new ALS treatments, whereas Biogen halted two pivotal Aduhelm studies early because of futility in its own function measurements. 

In general, to demonstrate substantial evidence of effectiveness of the drug, two adequate and well-controlled trials are needed. In Biogen's case, two adequate and well-controlled trials ENGAGE and EMERGE to evaluate the efficacy and safety of aducanumab in patients. When two studies gave contradicting results (one positive and one not positive), a third adequate and well-controlled study will be needed (before the drug approval, not after the drug approval). I remembered other examples: Pirfenidone was developed for treating the rare disease of IPF (idiopathic pulmonary fibrosis). The sponsor conducted two pivotal studies with one study positive (p=0.01) and one study negative (p=0.5). Initial NDA submission with these two studies was rejected by the FDA. FDA demanded the sponsor to conduct a third study. A third study gave a positive result (p<0.01) and NDA was resubmitted, and FDA approved the Perfenidone for IPF. Another example is ciprofloxacin dispersion in non-CF bronchiectasis (rare disease without approved treatment). The sponsor conducted two identical phase III studies ORIBIT-3 and ORBIT-4 - two studies gave contradicting results (one positive and one not positive). The NDA was rejected by FDA and additional studies were not conducted due to funding issues - ciprofloxacin dispersion remains not approved for non-CF bronchiectasis. 

In Biogen's case, two years have passed since they revealed the results of their pre-maturely discontinued studies: one with positive and one with negative. They could have started the third study and would be able to complete the third study not far from now. Instead, with FDA's help, they got their aducanumab approved without doing the third study and they were given a long 9-years to do a post-marketing phase IV study.

References:

• The Saga of Biogen’s Alzheimer Drug Aducanumab
• FDA advisory committee meeting on Biogen's aducanumab in Alzheimer's Disease
• Aducanumab approved label
• FDA aducanumab review documents
• Letter to AdCom "Accelerated Approval of Aducanumab NDA for Alzheimer’s disease"
• Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry
• FDA Guidance: Expedited Programs for SeriousConditions – Drugs andBiologics
• Listen: Two Alzheimer’s experts with opposing viewpoints on Aduhelm
• Podcast: Every angle on the FDA's polarizing approval of Biogen's Alzheimer's drug

Within Patient Benefit-Risk Evaluation? Using Outcomes to Analyze Patients versus Using Patients to Analyze Outcomes?

In our daily life, benefit-risk evaluation is something we always do whether we realize it or not. Benefit-risk evaluation is especially critical in drug development and in the regulator's decision process. We often hear that a drug is approved because the benefits outweigh the risks. In the recent decision of resuming the J&J Covid-19 vaccine, the CDC and the FDA cited that the benefits of rolling out the J&J Covid vaccine outweigh the risks of developing the rare blood clot (so-called CVST Cerebral Venous Sinus Thrombosis) in some young women who received the J&J Covid vaccine. 

In a recent New York Times article "Irrational Covid Fears", the benefit and risk of the Covid-19 vaccine are compared to a fable of our times and automobiles. 

A fable for our times

Guido Calabresi, a federal judge and Yale law professor, invented a little fable that he has been telling law students for more than three decades.

He tells the students to imagine a god coming forth to offer society a wondrous invention that would improve everyday life in almost every way. It would allow people to spend more time with friends and family, see new places and do jobs they otherwise could not do. But it would also come with a high cost. In exchange for bestowing this invention on society, the god would choose 1,000 young men and women and strike them dead.

Calabresi then asks: Would you take the deal? Almost invariably, the students say no. The professor then delivers the fable’s lesson: “What’s the difference between this and the automobile?”

In truth, automobiles kill many more than 1,000 young Americans each year; the total U.S. death toll hovers at about 40,000 annually. We accept this toll, almost unthinkingly, because vehicle crashes have always been part of our lives. We can’t fathom a world without them.

It’s a classic example of human irrationality about risk. We often underestimate large, chronic dangers, like car crashes or chemical pollution, and fixate on tiny but salient risks, like plane crashes or shark attacks.

One way for a risk to become salient is for it to be new. That’s a core idea behind Calabresi’s fable. He asks students to consider whether they would accept the cost of vehicle travel if it did not already exist. That they say no underscores the very different ways we treat new risks and enduring ones.

I have been thinking about the fable recently because of Covid-19. Covid certainly presents a salient risk: It’s a global pandemic that has upended daily life for more than a year. It has changed how we live, where we work, even what we wear on our faces. Covid feels ubiquitous.

Fortunately, it is also curable. The vaccines have nearly eliminated death, hospitalization and other serious Covid illness among people who have received shots. The vaccines have also radically reduced the chances that people contract even a mild version of Covid or can pass it on to others.

Yet many vaccinated people continue to obsess over the risks from Covid — because they are so new and salient.

This article reminds me of the seminars presented by Scott Evans. In his seminars, for example, the one posted on youtube, he started with a hypothetical question:

If you are given a choice to choose drug A or drug B, Drug A increases your intelligence, but decreases your good looks; Drug B increases your good looks, but decreases your intelligence; which drug will you choose? 

This is a typical question about the benefit-risk evaluation or benefit-risk tradeoff. With this question, he brought up a topic about an alternative (supposed to be optimal) way to perform the benefit-risk evaluation (i.e., the benefit-risk assessment on each individual patient level before aggregating the data on the group level).  

• Using Outcomes to Analyze Patients Rather than Patients to Analyze Outcomes: A Step toward Pragmatism in Benefit:risk Evaluation
• Methodologies for pragmatic and efficient assessment of benefits and harms: Application to the SOCRATES trial
• Pragmatic Benefit:Risk Evaluation: Healthy Disruption for Clinical Trials and Diagnostic Studies

Currently, in clinical trials, the benefit (efficacy) evaluation and risk (safety) evaluation are performed independently. The study protocol was designed for showing the benefit (efficacy) - selecting the sensitive and clinically meaningful efficacy endpoint, ensuring sufficient large sample size for statistical power, sound statistical analysis methods are all for ensuring that the efficacy results can be used to demonstrate the benefit of the new drug. FDA has issued specific guidance only for efficacy "Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products".

Risk (safety) evaluation is usually assessed separately from the efficacy. While we collect the data for risk (safety) analysis (adverse events, serious adverse events, death, clinical laboratory results, ECG results, vital signs,...), the analyses of safety data are usually based on the summaries (no hypothesis testing) to assess the nature/pattern of the serious adverse events, related to the investigational new drug, if there is elevated levels in certain laboratory parameters,... Safety analyses contain a lot of subjective judgment. Different reviewers may come to different conclusions. 

There is no separate guidance from FDA specifically about the risk (safety assessment). Instead, the safety assessment is included in FDA's Good Review Practice: Clinical Review Template - a checklist for FDA reviewers in evaluating the safety. 

Only after the efficacy and safety are separately analyzed and evaluated, are a benefit-risk section written as a formal evaluation of the benefit-risk - this is usually in CTD module 1 and 2. 

This approach of assessing the efficacy and safety separately evaluates the average effect (efficacy or safety) in the entire study population. The benefit or risk can not be easily translated into the individual patient level. In clinical trials, it is almost impossible to decide if a drug is good (the benefit outweighs the risk) for a specific patient. We have to wait for the aggregate data to determine the benefit and risk on a group level. 

With advances in precision medicine and pharmacogenomics, we hope that in the future, within-patient benefit-risk evaluation can be performed. In the present days (perhaps the foreseeable future), the benefit-risk evaluation (or efficacy-safety evaluation) will still be primarily based on the population level to assess the average group effect. 

• Average effect (Using Patients to Analyze Outcomes)
• Subgroup analyses to identify the prognostic factors (phenotypes) to help identify the patients who will more likely to respond to the therapy with fewer side effects
• Targeted therapies, Precision Medicine to identify the genetic biomarkers (genes) to help identify the subgroup of patients who will more likely to respond to the therapy with few side effects  
• Individual effect - within patient benefit-risk evaluation 

Even with targeted therapy, it is still not possible to be certain if a therapy will be good (the benefit outweighs the risks) for a specific patient. 

For the J&J Covid-19 vaccine issue, it seems to be clear that the vaccine does appear to increase the risk of the rare blood clot - CVST. Since the CVST is so rare, the benefit of receiving the Covid-19 vaccine outweighs the risk of the rare blood clot - this assessment is on the population as a whole. When it comes to the individual person, it will be his/her own choice - the risk is small, but maybe there.