Four emerging challenges to the FDA posed by COVID-19

The FDA and US life sciences industry are moving at breakneck speed to try to bring new treatments, cures and vaccines to market for COVID-19. But even as regulatory hurdles are cleared or lowered, there are many challenges ahead for both the FDA and industry. In this analysis, AgencyIQ looks at four challenges the FDA and industry are likely to face in the coming weeks and months, and how those challenges might be met.

To contact the author of this analysis, please email Alec Gaffney (agaffney@agencyiq.com).

Challenge #1: Public expectations to get new medical products approved quickly

Perhaps no aspect of the FDA’s COVID-19 response will be scrutinized as heavily or widely as its reviews of medical products, as well as the speed at which it conducts those reviews.

Here, the FDA is likely to find itself in an almost impossible position:

  • The speed at which it approves, clears or authorizes a product will be seen as too slow for critics who see the regulatory body as standing in the way of patient access for critically needed therapies;
  • Any rejection of a product—including those that are demonstrated to be potentially dangerous and have uncertain benefit—will be questioned by the public (and, potentially, lawmakers) as being incorrect and presumptuous; and
  • Any failure of a product, such as approval of a product that goes on to harm patients or one that does not perform as advertised, will be cited as proof that the agency isn’t performing as it should be.

For regulators at the FDA, this pressure is likely to be relentless. In the short-term, the agency is under tremendous pressure to increase testing capacity for diagnostic devices and facilitate expanded access to medical products. In the medium- to long-term, it will be under pressure to approve new therapies and vaccines.

Ordinarily, the development process for those products takes years, involves extensive testing, and progress on therapies is typically only of interest to a select subset of patients and investors.

Now, the entire world will be closely watching data about vaccine efficacy and safety as part of a critical test to enable the resumption of the core functions of society. For better or worse, every action taken by the FDA to bolster or block a product will be subject to scrutiny.

This is likely to be of particular interest to both Congress and the White House. President Donald Trump has already been a fierce advocate for the use of hydroxychloroquine, an anti-malarial for which some studies have suggested could modestly improve clinical outcomes in certain patients with COVID-19.

“What do we have to lose?” the President asked during one press conference in April 2020. “It is a very strong, powerful medicine. It does not kill people. We have some very good results and some very good tests.” The data, however, are inconclusive and also indicate that some patient experience serious side effects.

Some legislators have also been advocates for the drug, including Sen. Ron Johnson (R-WI), who has requested that President Trump ask the FDA to expand the scope of the product’s current Emergency Use Authorization.

Whether recently-appointed FDA Commissioner Stephen Hahn can withstand the intense pressure from outside the agency remains to be seen. Unlike other recent FDA Commissioners, Hahn did not come to the agency with extensive prior government experience and has not yet been able to build deep relationships with legislators and other government officials who might otherwise be able to help him to navigate competing demands on the agency.

 

Challenge #2: What happens if something goes wrong?

Even under the best-case development scenarios, the FDA is unlikely to have a cure or vaccine available for COVID-19 until some time in 2021. But drug and biologics development is phenomenally complex and often subject to unexpected setbacks. 

Under ordinary circumstances, only about 33% of vaccine products that enter Phase 1 clinical testing go on to receive approval.

But suppose the best-case scenario doesn’t happen. What then?

There are several likely scenarios that could confront the FDA in the next several months (or years) that could present significant challenges:

  • A product is thought to be promising based on early data, but subsequent testing in pivotal trials finds evidence of significant safety risks.
  • A product is approved based on limited data in several thousand patients. However, when it is used in millions of patients, it is found to have limited efficacy in certain patients or demographic groups, as well as rare or serious side effects.
  • A product is approved and is safe and effective, but manufacturing issues cause the product to be ineffective in patients who receive the sub-standard dose.

Each of these issues could shake public confidence in the abilities of both industry and the FDA.

With so much media attention on potential treatments, the public could believe that a product is likely to be effective based on early-stage clinical data, despite more statistically significant late-stage clinical data on the same product that could become available later. A vaccine product that causes a rare side effect could shake public confidence in other medical products, including both those intended to treat COVID-19 and those intended to treat other conditions. Already, a portion of the public expresses unfounded beliefs that vaccines cause deleterious effects like autism. Issues with a COVID-19 vaccine could exacerbate underlying hesitancy about the effectiveness of vaccines in general.

One potential problem is the scale of a product’s potential use. Any COVID-19 vaccine, for example, is likely to be used by tens—even hundreds—of millions of patients. At this scale, even a safe product which causes adverse events in just 1% of patients is likely to cause a large number of adverse events.

And then there’s the problem of time. As public officials promote the potential for COVID-19 treatments and vaccines to become available by 2021, they run the risk of promising that which may not be delivered. Setbacks could easily cause a vaccine to not be approved until 2022 or later. As ongoing investments in HIV prevention research have shown, sometimes vaccine development presents unique challenges that aren’t easily addressed over time.

Both the FDA and industry will need to be careful in their messaging to ensure the public is realistic about their expectations for medical products, the safety and efficacy of those products, the timelines for development, and the potential setbacks which may occur.

 

Challenge #3: Routine regulatory actions will be scrutinized like never before

As industry begins clinical development for dozens of products to treat, prevent or cure COVID-19, regulatory actions that are usually only tracked by investors, regulatory and market intelligence professionals and regulators are becoming subject to intense interest and scrutiny from other stakeholders.

Much of that interest is coming from persons or groups broadly unfamiliar with how the FDA ordinarily operates, the purpose of certain actions, and the impact of an action (or inaction) by the FDA.

Already, companies have begun to see the effects of public increased scrutiny and interest. For example, in March 2020 the biopharmaceutical company Gilead Sciences obtained Orphan Drug Designation for an investigational product, remdesivir. Ordinarily, a sponsor seeks that designation as a means to receive additional federal tax credits, avoid certain testing requirements (for pediatric studies), and receive seven years of marketing exclusivity. However, public outcry about the potential for the company to restrict access to its drug under the exclusivity provision prompted the company to rescind its request for the designation, with the FDA complying soon after.

As AgencyIQ has previously explained, companies are likely to soon face a similar headache over another regulatory designation known as Breakthrough Therapy Designation. Breakthrough designation allows manufacturers to receive benefits including FDA assistance designing their clinical trials, more frequent meetings with the agency, “rolling reviews” intended to help minimize administrative delays, hands-on interaction by FDA staff to help minimize issues as they arise, and eligibility for priority review (which accelerates a review by 4 months). To qualify, a company must meet specific eligibility criteria. Most products in clinical testing for COVID-19 are likely to meet that criteria, according to AgencyIQ’s analysis.

However, the word “breakthrough” is just as likely to cause confusion among the public, who could believe that a literal “breakthrough” is on its way. In reality, the name was established by Congress and doesn’t reflect a belief that a product is (or is not) a breakthrough.

In general, companies and the FDA will need to become more effective at communicating with the public. Whereas most traditional stakeholder communications target regulatory-savvy investors or media who focus exclusively on FDA topics, most readers of COVID-19-related communications are likely to have limited context in which to understand the importance of specific regulatory developments. Companies in particular should look to contextualize developments and explain them in plain language. Without it, some members of the media will find it difficult to figure out what matters and what doesn’t.

 

Challenge #4: How does COVID-19 impact the FDA and product reviews?

The longer social distancing measures are in effect, the more likely it is that the FDA’s ordinary operations start to see major disruptions.

In general, there are several ways in which COVID-19 might serve to disrupt the functions of the agency and industry:

  • The FDA is currently unable to conduct its normal Pre-Approval Inspections for medical products. These inspections are generally conducted to ensure a manufacturing site is capable of making a new product, and that the data used to support an application for approval was not falsified. The FDA may be forced to delay the approval of some products or adjust its expectations for what a PAI includes (such as a paper-based inspection).
  • As the FDA shifts its focus to review products for COVID-19, some staff could be re-assigned from their current review workload to focus on products intended to respond to the pandemic. That could, in turn, affect either review timelines or the expertise available for specific reviews. It might also be more difficult for the FDA to hire new staff to replace those leaving the agency in the interim due to operational challenges related to COVID-19.
  • Clinical trials are in some cases already being delayed or stopped early by COVID-19. This could push product timelines back, causing a decrease in applications for approval in the coming years.
  • As COVID-19 dominates the FDA’s focus for the next several months or years, it remains unclear which other FDA priorities, including planned guidance documents and regulations, might be postponed. The FDA was working on a swathe of major policies to permit the importation of certain prescription drugs from Canada, for example, which were expected to be released prior to the 2020 election. The FDA was also planning a major shift toward a new medical device quality system. It’s unclear which, if any, of these efforts will continue on apace, and which will be delayed.

A return to normalcy may prove difficult for the FDA in particular. The political pressures and public scrutiny directed at the FDA may set significant new precedents that could prove challenging to undo. For example, if the FDA is able approve medical products for COVID-19 extremely quickly, that could put pressure on it to accelerate the review of other products (for as those for cancer or other serious conditions) in the future.

The agency is also likely to have a backlog of meetings to conduct and policies to create, all of which could take months or longer to clear.

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