Need to know:
- At this stage of the pandemic, there are almost 1,500 industry-sponsored clinical trials investigating Covid-19 vaccines or therapeutic assets, and most of these are in the early phases or in planning stages.
- Clinical Trials Arena spoke to regulatory experts on how the possible closure of EUA would affect Covid-19 clinical trial plans. They offer advice on how sponsors can keep their research pipelines moving forward in the event EUA start to shutter.
The FDA’s Emergency Use Authorization (EUA) allows Covid-19 vaccines and therapeutics to enter the market quicker than the usual pathway of full licensure. But as the government and the public look to shift into an endemic state, questions arise as to the future of this regulatory trail.
The most clear-cut signal as to when EUA doors may shut is when the pandemic is officially declared over. Yet health leaders are having to tread carefully as how or when this might happen. Last week, Dr. Anthony Fauci, the US president’s chief medical advisor, stated that the US is stepping out of the “full-blown explosive” Covid-19 pandemic phase, but one day later clarifying his statement by saying that the country is still in the pandemic.
Timelines as to when EUAs will no longer be available or given out to a limited number of assets is critical for clinical trial sponsors, as it is a key element on how they design their trials and shuffle their pipeline plans. There are 1,455 industry-sponsored clinical trials that are investigating Covid-19 vaccines and therapeutics, and nearly half of them still in the planning stage, according to the GlobalData Clinical Trials Database. GlobalData is the parent company of Clinical Trials Arena.
Further, a significant majority of the trials are in early phase, which raises the question if they could miss out on an EUA once they are at the stage when they are ready to file for one. Futureproofing one’s clinical trial is vital, especially for small- to medium-sized pharma sponsors, who will have to make calculated decisions to steer clear of clinical development and financial risk.
Uncertainty over EUA pursuit lingers
The EUA pathway allows the FDA to authorise unapproved medical products to protect the public from health emergencies. Since March 2020, when the Covid-19 EUA declaration came in effect, there are 14 therapies with an EUA and three different vaccines, by Johnson & Johnson, Moderna, and Pfizer with BioNTech, with an EUA, with the latter two now fully approved.
There are therapies with revoked EUAs. Hydroxychloroquine, AbCellera Biologics and Eli Lilly’s bamlanivimab, GlaxoSmithKline and Vir Biotechnology’s sotrovimab, and Regeneron’s REGEN-COV had their EUAs rescinded due to decreased efficacy against new variants. Gilead Sciences’s Veklury (remdesivir) has its EUA limited to certain Covid-19 patients.
At this stage of the pandemic, small- to medium-sized clinical trial sponsors that are targeting to get an EUA for their Covid-19 products are at risk of a financial hit, says former FDA director of The Office of Vaccine Research and Review Norman Baylor, PhD.
While there are no clear signs when the FDA is planning to close the EUA pathway, smaller companies should assess their risks of entering the Covid-19 development race, all the way to market, as their products would be competing with vaccines and therapeutics already established in the market, Baylor, who is now the CEO of Biologics Consulting, notes.
Baylor adds the market value of an EUA is also pertinent in those who are awaiting an EUA decision. Indeed, companies will have to decide if it is justifiable to release a product a few months earlier under the EUA or delay the product and wait to get a full approval, says Dorit Reiss, PhD, professor of law at UC Hastings College and a member of the Vaccine Working Group on Ethics and Policy.
Reiss explains that products with an EUA can be perceived by the public as rushed and experimental due to their expedited investigations, which can persuade some companies to pursue full licensure instead; however, the latter is more costly and time-consuming. “It is a balance between waiting and letting people die and approving it knowing that some people will see it as rushed,” she elaborates.
Even if the EUA pathway remains open, companies themselves might avoid going for one altogether, says professor of law at Boston University Christopher Robertson. There might not be a lot of upsides for the companies to complete additional time-consuming paperwork to secure an EUA when the public health emergency door is closing, he explains.
Changing clinical trial gears if EUA motorway closes
EUA changes would be based on Covid-19 no longer being an emergency, which would suggest that the market is also shrinking, Robertson says. In the past few months, there has been a slowing uptake of Covid-19 vaccines in the US. Certain therapeutics’ uptake also has been slower than expected, as seen with Pfizer’s antiviral Paxlovid, but its complex eligibility requirements have been identified as the main culprit.
Robertson explains that focusing on one single pandemic is not beneficial for a business in going forward. Companies should start assessing if their investigational product and its technology could be repurposed and studied in a new clinical trial, he adds. Even in companies with an EUA, they are already looking at repurposing their assets: Moderna is investigating its mRNA technology in influenza, HIV, chickenpox, herpes, and many more. Demonstrating the asset’s efficacy and value in other indications can help the company to shift from an emergency frame of mind to a longer game plan, Robertson adds.
Partnering with bigger pharma on future clinical trials is a potential solution for small- and medium-sized sponsors. Established pharma companies bring capital, regulatory, and marketing expertise that can help smaller, innovative companies to bring their assets to the market and compete with bigger players, Robertson says. As an example, BioNTech’s Covid-19 vaccine asset was put on the development fast track with the help of Pfizer’s resources.
But there are also arguments for companies to stay on the path of designing their clinical trials to secure an EUA. Assets in the early stages of development still have a chance of being successful Covid-19 products, especially if they have an easier way of administration or lower price point, says healthcare consulting firm Avalere principal Kelly George, PhD.
Mapping an asset around a targeted population, from choosing endpoints all the way to reimbursement, are important strategic steps, George adds. Companies should continue to develop their product if it can help with unmet need and fill in a gap in the global pharma market, she says.
If EUAs are no longer available, the FDA’s Expanded Access, sometimes called compassionate use, is a solution companies could consider, Robertson suggests. However, under such pathway companies are not allowed to profit, which might not serve their long-term interests, he explains.
End of Covid-19 EUAs
The issuance of EUAs falls under the section 564 Food, Drugs, and Cosmetics (FD&C) Act, which does not have an expiry date, unlike the 319 Public Health Service (PHS) Act declaring a Public Health Emergency (PHE), which must be extended every 90 days if needed, George explains.
Clinical Trials Arena reached out to the FDA for a comment, but the agency referred to its latest EUA guidance. According to the FDA website, the EUA declaration is not dependent on the PHS Act, meaning that EUAs can be issued beyond the duration of 319 PHS declaration, if there are no adequate, approved and available drugs to protect from or treat a public health threat. A few months’ notice will be issued before the EUA declaration is terminated as all products under EUA will become invalid and manufacturers need time to apply for full licensure, George explains.
The agency’s decision on the future of EUAs will likely depend on what value current vaccines and therapeutics offer to the public, Harvard Medical School assistant professor Jonathan Darrow says. Baylor notes that it is hard to predict when the public health emergency will end or when the FDA will stop granting EUAs.
And this is especially true with the emergence of new variants, Baylor adds. If there are licensed and available vaccines or therapeutics with ample supply to provide to the target population, the FDA could theoretically stop granting EUAs, he notes. However, while there are licensed products for adults, there are none for the pediatric population, which would suggest the need for EUAs, he says.
Reiss notes, while speculative, that the FDA might grant one more EUA for a non-mRNA Covid-19 vaccine, as an alternative to mRNA vaccines, and since Johnson & Johnson’s adenovirus-vectored vaccine is not covering much of the market. She adds that EUAs will still likely be granted for therapeutics but highlights vaccines and therapeutics do not substitute for each other as they are both needed.
While some mistakes were made along the way, such as the authorization of hydroxychloroquine, the EUA was the best tool available to tackle Covid-19 in the past two years, experts say. The EUA has shown itself as the ideal approach for future health crises, but further global collaboration and clearer regulatory requirements need to be specified, they add.
Any previous EUA hiccup shows a functioning system and framework of regulators continuously reviewing data and making informed decisions before giving a full approval to a product, George notes. But as the world slowly transitions into a new phase of the pandemic, pharma companies will be kept on their toes in this possible last stretch of the EUA race.