Examining the FDA’s Drug Approvals Process

The agency’s request for a review of the approvals process for the monoclonal antibody aducanumab is the latest twist in an unprecedented saga involving the Alzheimer disease treatment. We asked a panel of experts to analyze the approvals process, explain the role of real-world data, and predict what the future may hold.

To say that aducanumab (Aduhelm, Biogen)—which recently received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of Alzheimer disease—has experienced a bumpy road since its approval would be an understatement. And it also appears the monoclonal antibody’s journey to acceptance and uptake in the industry will continue to be tumultuous.

Initial approval of aducanumab was broad, but eventually the FDA narrowed its recommendation to include only individuals with mild disease. Then, on July 9, acting FDA commissioner Janet Woodcock sent a letter to the acting inspector general of the Department of Health and Human Services requesting an independent review of aducanumab’s approval process. In a tweet, Woodcock said: “Given the ongoing interest and questions, today I requested that @OIGatHHS conduct an independent review and assessment of interactions between representatives of [aducanumab’s maker] Biogen and FDA during the process that led to the approval of Aduhelm.”

Even before the approval indication was narrowed and the investigation was announced, the lay press began reporting that aducanumab was poised to become either a game-changing medication or an expensive albatross backed by flimsy evidence. A recent editorial in The Wall Street Journal noted that aducanumab “could transform the disease from a death sentence to a manageable condition like diabetes or multiple sclerosis.” Meanwhile, a perspective in The New York Times said the drug’s approval is a sign “the FDA has progressively lowered its standards of effectiveness and safety required for drug approvals.”

With such prevalent controversy, we turned to the experts for clarification and analysis.

All of our panelists agreed that the FDA process has evolved over the years. This change, said Edmund J Pezalla, MD, founder and CEO of Enlightenment Bioconsult in Hartford, CT, “accommodates orphan disease programs with smaller trials [that have] single arms and [no] randomization." He added that these conditions, with fewer patients and more unmet needs, is more of a factor than accelerated approval. "The agency has continued to apply rigor to evaluation even when reviewing more quickly," he said. 

Gary Owens, MD, president of Gary Owens Associates in Ocean View, DE, agreed. “There is more emphasis on research and development of drugs for small populations, rare diseases, and oncology, since drugs in these disease states are likely to qualify for one or more accelerated approval pathways."   He pointed out that in 2020, 31 of 53 FDA-approved medications were for orphan diseases.

Quoting from the FDA press release announcing aducanumab’s approval, Larry Hsu, MD, medical director at the Hawaii Medical Service Association in Honolulu, noted “medications that ‘treat serious conditions, and that fill an unmet medical need’ based on ‘a surrogate or intermediate clinical endpoint’ can be considered for accelerated approval. In the FDA’s estimation, aducanumab qualified, and, explained Dr Hsu, “Patients now have access to a treatment that was not available before. The question is, does the drug allow for improvements in health care outcomes?”

David Marcus, director of employee benefits at the National Railway Labor Conference in Washington, DC, said that this approach complicates things for plan sponsors, insurers, and clinicians. “[They] are left to sort out if the drug is actually beneficial and they must do so in the face of pharmaceutical marketing and public pressure.” He added that these entities are forced to make decisions despite “the lack of timely reporting of clinical trial results.” They are handed “high-cost medications [that have no] incremental benefit.” 

Who Are the Real Beneficiaries?

The question up for debate is, why? To benefit patients? To improve the margins of the pharma company? Surely both can be true, and the real answer is likely nuanced. “Pharma’s business model is one where the goal is not necessarily to produce cost effective medications—it is simply to make drugs that are not harmful,” explained Mr Marcus. “Of course, safety is critical but the practical ramification of this process is a lower bar to market entry—not increased efficacy.”

Charles Karnack, PharmD, BCNSP, assistant professor of clinical pharmacy at Duquesne University in Pittsburgh, PA, concurred. “In my view, pharma's business model now includes greater financial rewards to stockholders and corporate executives at the cost of scientific rigor.”

Norm Smith, a principal payer market research consultant in Philadelphia, PA, said he believes the pressure is often not from stockholders, but advocacy groups. With aducanumab, “I think the FDA was caught up in the emotions of Alzheimer disease caregivers. These patient groups pushed for approval using what most clinicians would consider weak data. Aducanumab provides hope.”

Pharmaceutical companies have had to adapt their business model to the process that facilitates accelerated approval, said F Randy Vogenberg, PhD, RPh, principal at the Institute for Integrated Healthcare in Greenville, SC. “They also have to build their research pipeline over many years, which requires certainty and consistency over that long period.” Overall, “I think the process has evolved to a better model that assures both safety and efficacy of products for use in the US compared with other countries.”

Arthur Shinn, PharmD, president of Managed Pharmacy Consultants in Lake Worth, FL, agreed. “Years ago, I worked in the medical department of a major pharmaceutical company. The approvals process was cumbersome—the paperwork alone slowed things down considerably. Now, it is much more streamlined and I think that is a net benefit to the patient.”

Mr Marcus pointed to faster generic approvals and necessary streamlining as positives, which Dr Owens noted has been due to legislative changes—most recently the 21st Century Cures Act. The net result, he explained, has been mixed. On the plus side, a number of cancer drugs have recently been approved based on early and mid-stage trial results that have been shown to be beneficial to patients. However, this year two checkpoint inhibitors for locally advanced or metastatic urothelial cancer—atezolizumab and durvalumab—have been withdrawn. Both were approved for this indication under the accelerated approval program, but subsequent data did not show survival benefit.”

According to Dr Karnack, such withdrawals may be due to the fact that early data show that new drug treatment is not inferior to standard treatment, “instead of showing a positive statistical difference between the two groups representing a benefit to the patient.” But he, too, said he sees the upside of moving faster, and corporate involvement can help in that regard by investing in increased resources.

Analyzing the Process

Some, including Mr Marcus and Dr Karnack, think that the current clinical trials reporting and biosimilars approvals processes point to an erosion in the FDA process. “More critical thinking is needed to show how one factor—such as decreasing amyloid in the brain with aducanumab—may or may not affect outcomes,” said Dr Karnack. “Even the slightest signal should be pursued rigorously, especially in diseases where a lack of treatments exists.”

But erosion is too strong a term, noted Dr Pezalla. “There is a need for better ways to handle drugs in therapeutic categories with great unmet need, to develop more data before full approval, and to develop that data within a reasonable time frame.”

Dr Vogenberg turned his attention to the FDA itself, pointing out that a lack of appropriate expert and staffing levels makes it difficult for the agency “to keep pace with scientific progress and aggressive markets seeking cures not just remedies.” Dr Hsu said that the FDA does not always follow its recommended processes, and the aducanumab approval is a prime example. “The FDA usually follows the recommendations of outside panels. For aducanumab, the panel voted overwhelmingly against recommending approval, saying data failed to demonstrate persuasively that aducanumab slowed cognitive decline. Despite this strong recommendation of non-coverage, the FDA went ahead.”

“The FDA processes will always evolve,” surmised Mr Smith. “Clearly, it accepted Biogen’s data with its eyes open, knowing the data’s limitations.”

The Role of Real-World Data

Perhaps the FDA is counting on real-world data to fill in the blanks. “This is a reasonable approach based on the assumption that the FDA can require additional data from real-world studies and monitor those data,” said Dr Owens. He added that while this is a good approach for safety, how well it works for efficacy is uncertain. The FDA can require such data, but its ability to force its collection is weaker. This, noted Dr Owens, was underscored in a 2017 study showing that of the post approval requirements requested by the FDA in 2009 and 2010, only 54% were completed by 2015.

“Real-world data can certainly be part of an intermediate step before full approval but there needs to be more discussion of how real-world studies are conducted and evaluated,” explained Dr Pezalla. “We need rigorous standards from the FDA for studies that will result in full approval and a public discussion of how those studies are evaluated.” Mr Marcus agreed. “Real-world experience needs to be analyzed as robustly as data from a randomized clinical trial. Getting trial information into the hands of clinicians and having a process that allows for responsible administration to patients would be useful, versus the vacuum clinicians are often operating in.” Dr Shinn concurred. “The key is collecting and analyzing real-world data.”

It’s important to note, said Dr Vogenberg, that the concept of real-world evidence has existed for some time “but has not been fully utilized until recently. It was a solution in search of a need—until COVID-19.  Now there is renewed urgency to move forward faster on drug approvals where safety seems assured, leaving only the extent of efficacy in question. That is something that real-world evidence can clearly determine.” Dr Karnack agreed, provided that safeguards are in place, including post-marketing surveillance and increased patient participation. He added that specialty pharmacies can help with the latter.

Can Stringent Prior Authorization Counterbalance Accelerated Approval?

Mr Smith thinks real-world experience will not help much with aducanumab, since the drug “slows the decline, but does not reverse it. What intermediate indicators would be of value to payers?“ For that reason, he said, the controlled trial data will be of most value to insurers. Mr Smith said he expects the prior authorization process for aducanumab to be stringent, perhaps to a fault. He noted that the same is occurring with PCSK9 inhibitors and serves as a model for “disincentives to use.”

So, is the natural tension that exists between accelerated approval and stringent prior authorization enough? Dr Owens said he would have favored a more deliberate approach for aducanumab approval.  The chain of events since approval supports this approach, he added. “House of Representatives inquiries have been launched and at least two US senators have requested an analysis of aducanumab’s budget impact.  Three prominent members of the FDA advisory committee that recommended against approval have resigned.” Moreover, he explained that in its recent draft evaluation of aducanumab’s phase 3 trial data, the Institute for Clinical and Economic Review stated that the price of the drug needs to be between $2500 and $8300 per patient per year in order to meet cost effectiveness thresholds. “That is nowhere near the $56,000 annual price that was stated after approval.”

At that price, stakeholders deserve “a more deliberate approach where approval [occurs] only with demonstrable benefit of cognition,” insisted Dr Hsu. Dr Pezalla said that the aducanumab approval process “points out that we lack a good way of balancing cost and access when there is a lot of unmet need. Cost is not, and should not, be an issue for the FDA. The agency needs to continue to focus on science. However, an intermediate step would help payers, including CMS [Centers for Medicare and Medicaid Services], seek lower prices for drugs without proven benefits.”

Dr Karnack said he worries about the slippery slope the FDA is now on due to certain approvals in oncology and now Alzheimer disease. “How many other potentially high-cost drugs could be approved with marginal benefit? I believe it is short sighted, gives patients false hope, and is detrimental to health care finance, since it uses funds that would be better spent on other disease treatments or different treatment strategies.” Rather than focus on a “one-size-fits-all” strategy, he wonders if a better approach is personalized medicine that has been successful in oncology or looking at treatments with different mechanisms. “With Alzheimer disease, the role of blood glucose regulation may have a greater impact than amyloid or tau proteins.”

A Blueprint for Future Approvals?

Still, aducanumab’s path may serve as a blueprint. It will increase the reliance on surrogate endpoints to get faster approvals, said Dr Owens. Mr Smith added, “Look for drugs that treat amyotrophic lateral sclerosis and Huntington’s disease to have similarly easier routes to approval.”

While surrogate endpoints can be valid, there will be times when they are not, noted Dr Owens. “We already have the most inefficient health care system in the world, and this seems to further drive another potential source of inefficiency.”

“This is an especially important issue at a time when public trust in science is teetering,” added Dr Hsu. Mr Marcus wondered if the questions about aducanumab’s efficacy would “throw cold water on pharma for a period of time.”

Save some cold water for the FDA, said Dr Vogenberg. It is reasonable to question the “reliability and credibility of government agencies who depend on political appointees or elected officials to get funding. “How can society be confident in the efficacy approval let alone safety determination for these high cost, potential low use drugs?  We are still not exactly sure what causes Alzheimer disease, so what makes us think we can manage or cure it?”

Dr Pezalla said it is a reminder of just how difficult medications for degenerative neurological conditions are to study. “They rarely result in providing clear endpoints. The outcome tends to be a reduction in declining function, which is difficult to measure.”

Returning to the question of patient benefit vs pharma profits, reaction was mixed:

• Dr Karnack: “It looks as if profit and influence causes potential conflicts of interest.”
• Mr Marcus: “Without question, this is about money. It feels as if pharma is selling false hope.”
• Dr Vogenberg: “Patient benefit remains a key element in the equation of gaining approval. At the same time, investor and pharma profits are borne by those same patients.”
• Dr Owens: “It is simply a fine line balance point between the two. If the evidence for patient benefit is weak, the needle needs to fall on the side of caution and approval should be delayed even in the face of public pressure and corporate drive for approval.”
• Dr Pezalla: “If patients don’t benefit there should be no profits. We cannot support drugs with high prices if they don’t have enough data to make good decisions about their use.”

COVID-19 Vaccines and Aducanumab: A Tale of Two FDA Approvals

This year may well be remembered as one where the pharmaceutical industry and the FDA were praised and ridiculed for acting swiftly. The mRNA vaccines that protect against COVID-19 are considered a modern miracle, developed and produced in record time to quell a public health and economic crisis. Emergency use authorization (EUA) of the COVID-19 vaccines is praised by many. Meanwhile, accelerated approval of aducanumab, based on data showing it reduces amyloid plaques in the brain, has been met with significant scrutiny. 

In certain circumstances, moving swiftly makes sense—such as during a public health emergency, said Dr Pezalla. “But we should be careful to apply this experience to drug development in other circumstances unless we can conduct the appropriate trial within that sort of time frame.” 

Mr Marcus pointed out that in addition to the scale of the pandemic that prompted accelerated development, mRNA was not a brand-new approach. “Under these circumstances, EUA of the vaccine makes sense.”

Alzheimer disease, an irreversible and progressive disorder that afflicts an estimated 6 million Americans, is a significant problem without a cure. But the hard reality is that when it comes to the numbers, COVID-19 has trumped Alzheimer’s disease. “COVID-19 is a viral outbreak that affected every person in every country of the world,” said Dr Vogenberg. “How that is processed and acted upon is very different than it would be for a disease that affects comparatively few. The calculation of value needs to be determined, and usually is in the eye of the beholder.”