It was an unexpected morning on 7 June 2021. The US Food and Drug Administration (FDA), approved aducanumab as the first treatment for b-amyloid protein, which is associated with Alzheimer’s disease.
While some were happy to see the approval of the first Alzheimer’s drug for nearly 20 years, others were shocked at its lack of efficacy. Ten members of an FDA panel of experts had voted against the approval, while the remaining one voted ‘uncertain’. Three of the three quit protesting when the drug had been approved.
Many Alzheimer’s specialists agree with the FDA’s advisory committee and statistical reviewers that the FDA’s late-stage clinical trials were inconsistent and incomplete. Another trial was the next reasonable step, not approval. The well-intentioned policy of speeding drugs to market has gone wrong. It’s now past time to fix it.
The US House of Representatives and FDA have both launched reform efforts to reform the accelerated approval process. They are mostly focused on giving FDA the ability to cancel approval once a drug has been approved. While this is important, I believe that the key to reforming the accelerated-approval process is transparency and ensuring that companies evaluate actual clinical benefits. FDA must be more transparent about the information it collects, and the decisions it makes.
The accelerated-approval program expedites the approval of medicines for life-threatening, serious diseases. Instead of relying upon evidence that a drug prolongs life or reduces symptoms, US regulators base accelerated approbation on a “surrogate” marker (such as tumour shrinkage) that is considered to be’reasonably probable’ to indicate clinical benefits. Although the advisory panel that recommended against the approval of aducanumab wasn’t consulted or notified about the use of accelerated approval by the US regulators, it was not informed about whether b-amyloid was a suitable surrogate marker. However, FDA officials had previously discussed this strategy with Biogen (a drug company in Cambridge, Massachusetts) who is currently developing the drug. The FDA’s initial “label” that was issued to physicians for prescribing aducanumab did not reflect the way the drug had been tested. It didn’t specify that patients should undergo an assessment for amyloid or disease stage.
A third of those who have taken aducanumab suffer from brain swelling and bleeding, which can lead to death. FDA is required to take into account patient feedback on how unproven benefits compare with potential risks. After a listening session with caregivers and patients, the FDA approved the FDA’s approval. There is no public report on this meeting. The Alzheimer’s Association, an Illinois non-profit, organized the session. It has received funding from Biogen and other companies working on similar treatments. The US government is investigating whether there were any improper interactions between Biogen, FDA. Both organizations insist that the process was correct. It is not uncommon for patient advocacy groups to be funded by drug companies that work on relevant diseases.
Initiated in the 1990s to accelerate HIV drugs that reduce viral load to market, accelerated approval is growing in popularity. Between 2005 and 2010, about five of these approvals were made per year. This approval was used to approve a dozen drugs in 2020. In 2019, a 2019 study found that only 19 of the 93 cancer treatment accelerated approvals from 1992 to 2017 had improved overall survival rates (B. Gyawali and al. JAMA Intern Med. 179, 906-913; 2019). The FDA approved Duchenne muscular disorder in 2020 despite warnings from experts. Drug companies can charge up to US$100,000.000 per year without showing that patients will live longer.
The FDA decides whether a drug’s safety and effectiveness is a standard approval. Accelerated approval has a different premise. To get quicker access, patients must accept uncertainty. In other countries, access to such drugs is patient-by–patient. However, ‘compassionate usage’ regulations permit clinicians to argue for individual prescriptions. Accelerated approval is a compromise between incomplete information and innovation that could meet unmet medical needs. The FDA must not be co-opted by commercial interests or unwarranted enthusiasm to obtain approvals when negotiating this balance.
The FDA should be recast as the guardian and information provider, ensuring more transparency in its decision-making process and that drug companies provide information on clinical benefit to reduce this risk. An announcement and label for drugs that have been granted accelerated approval should clearly state that there is no clinical benefit. The label for aducanumab says: “Continued approval of this indication may be contingent on verification of clinical benefit(s ).”) Drug companies have little incentive or motivation to complete those confirmatory studies.
The FDA must be transparent with its advisory committees regarding plans for accelerated approval and fully explain any decisions that are against the recommendations of advisory committees. This process should not be used as a back-up for standard approval’s failure to get a supportive vote. All accelerated approvals should be accompanied with a plan for confirmation trials that will evaluate whether the surrogate marker change has clinical value. This is how we can ensure that treatments lead to a happier and longer life.
