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.
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.
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