It’s not an understatement to say that the coronavirus disease 2019 (COVID-19) pandemic has been—and continues to be—a challenge for the US and the world. It has upended many of our critical structures, including our health system and medical treatments.
But for organizations such as the US Food and Drug Administration (FDA) and connected institutions conducting clinical trials, some procedures have had to change because of restrictions imposed by the pandemic and a new urgency to get some products to the public as quickly as possible.
It’s a balancing act. What remains to be seen is how these challenges have changed the FDA and whether the FDA has been altered forever when it comes to approving new drugs.
There’s no question that the COVID-19 pandemic has forced the FDA to streamline its procedures and update its processes.1
Like the employees of nearly every other organization in the nation, the FDA’s internal office staff has been affected by the pandemic. With work transitioning to remote mode, mandates disrupting travel, and fewer onsite inspections occurring, the FDA had to determine how to continue their work.
But FDA staff also needed to focus on the emergency at hand, and vital resources were shifted to deal with the pandemic’s new demands.
Attorney Chad Landmon, chair of intellectual property and FDA practice groups at Axinn, Veltrop & Harkrider, says that he saw the FDA accelerate its work on COVID-19 therapies and vaccines.2
That speed, however, meant more resource allocation to pandemic-related needs, with work on
non‒COVID-19 vaccines and treatments slowing.
The FDA also relaxed several of its own approval regulations to cope with the public emergency, including:
The FDA considered conducting virtual inspections but found them to be not especially successful.4
In the spring of 2020, clinical trials were suddenly thrown into disarray by the growing pandemic. Clinical trial enrollment and data collection were severely limited or restricted as stay-at-home orders were issued throughout the US.
Many potential clinical trial subjects suddenly found themselves unable to participate as studies were put on hold. This was a huge disappointment to those with cancer, dementia, stroke, and other serious illnesses, many of whom rely on trials as their best chance for improved health when other treatments have failed.
In April 2021, ClinicalTrials.gov listed 1773 suspended clinical trials, many of which noted the pandemic as the primary reason.5
Even trials that weren’t suspended faced challenges with both enrollment and data collection that required in-person contact.
Was clinical study participation worth the chance of coronavirus exposure? This wasn’t—and still isn’t—an easy question to answer.
Some researchers were able to modify their protocols after the FDA released guidelines that allowed more flexibility during the pandemic.6
For example, a few chose video and other remote options to collect data, with some success, but it’s still unclear whether they’re safe and accurate.
Yet some of these remote data-collection options may actually encourage subject participation, by eliminating the challenges of transportation and navigation of a large medical school that are considered barriers by some potential participants.
The FDA oversees one of the fastest drug approval processes in the world, with many becoming available in the US before Canada or Europe.7
Even so, the agency saw the need to establish the Coronavirus Treatment Acceleration Program (CTAP) to assist manufacturers in navigating administrative requirements and to expedite the review process.
What did this mean for other pipeline drugs seeking approval for other diseases?
In the early days of the pandemic in 2020, drugs for treatment of other disease states weren’t delayed much, if at all, in part because many of the facilities involved in production had recently been inspected or had a strong history of quality.
But that’s no longer the case: Clinical trials for other disease states have also been affected, mostly by the restrictions imposed on participants and researchers because of COVID-19.
In fact, FDA inspection slowdowns have delayed approval of some new products in 2021.
Production of therapies for disease states ranging from high cholesterol to large B-cell lymphoma, schizophrenia, and bipolar disorder has slowed because the FDA was unable to inspect production facilities in the US and abroad.4
The FDA has predicted that approvals might be delayed as long as 4-6 months—but even that could fluctuate as the pandemic continues.
It’s no surprise that the major focus in recent months has been on the development of COVID-19 treatments, especially since the creation of CTAP.
Reduced approval times for COVID-19 therapies and vaccines demonstrate what’s possible, raising the bar as the FDA has expedited approvals based on an increasingly limited number of clinical studies. They then rely on the real-world evidence that emerges later.
But the news is not all dire for drugs not related to COVID-19.
In fact, the FDA approved 53 new non‒COVID-19 drugs in 2020—the second most in a single year after 2018’s group of 59.
This momentum continued through the first half of 2021; with the FDA endorsing its 29th novel drug on June 30, the industry was slightly ahead of last year’s pace.8
Of course, some drugs were made available to the public in late 2020 and early 2021 through a different route—the Emergency Use Authorization (EUA).
An EUA is one way for the FDA to make certain medical products available quickly (and temporarily) during a public health emergency. One vital aspect of an EUA: When it’s issued, it means that there are no other adequate, approved, or available options.9
The key here is that FDA drug approval through an EUA is based on substantial evidence that the drug is effective for its intended use and that the benefits of the drug outweigh its risks when used according to the product’s approved labelling.
The ideas that led to the creation of the EUA have been around for decades.
One noteworthy forerunner of the EUA was the AIDS crisis. In the late 1980s, an investigational drug called DDI (didanosine) was seen as potentially helpful to patients with AIDS who couldn’t tolerate other drugs. Director of the National Institute of Allergy and Infectious Diseases Dr. Anthony Fauci suggested a new “parallel track” for patients to start receiving the drug while it was still being studied.10
Years later, reports of potential pandemics (eg, swine flu) and other emergencies emerged alongside research on therapies for those illnesses.
In fact, it wasn’t until 9/11 and the “War on Terror” that Congress gave the FDA that specific power. The focus then, however, was on the threat of bioterrorism, not on a naturally occurring pandemic.
And so Congress approved the Project Bioshield Act of 2004, which called for billions of dollars in appropriations for purchasing vaccines in preparation for a bioterrorism attack and for stockpiling of emergency countermeasures.10
The EUA was used only a few times over the next 16 years; in 2009, when the H1N1 influenza virus (ie, swine flu) threatened to become a worldwide pandemic, the EUA allowed existing influenza drugs to be authorized for infants with H1N1.
The EUA was also used for medical equipment and influenza drugs in anticipation of Middle East respiratory syndrome, or MERS, Ebola virus disease, and Zika virus disease—none of which materialized in the US.
But it was only during the COVID-19 pandemic that an EUA was granted for new vaccines. 10
So what must happen for the vaccines, already used worldwide in millions of recipients, to receive final FDA approval? While the EUA gets the vaccines out faster, it doesn’t mean that any steps are skipped that would prevent full FDA approval in the future.
In the case of the 3 COVID-19 vaccines that received an EUA (Pfizer-BioNTech, Moderna, and J&J), each manufacturer enrolled tens of thousands of participants in randomized clinical trials. Those trials were similar—if not virtually identical—to studies that would have been performed for outright license approval.11
It’s interesting to note that the EUA process and the traditional FDA vaccine approval process have similar beginnings, although they differ later.
Similarities:
Differences:
Both Pfizer and Moderna applied for the FDA “Fast Track” process, which allowed them to submit portions of their information for final FDA approval as it became available.
In the end, it’s clear that the FDA reviews much more data, covering a longer period, before granting full approval.
The outlook from the pharmaceutical industry has been relatively optimistic as the US moves forward with the reality of living with COVID-19 for years to come.
In a 2021 survey by BDO, 100 chief financial officers at medium-to-large life sciences companies found that seven of 10 companies plan to increase spending on COVID-19 treatment and vaccine research and development and that about one-third have already done so.
However, a large number of companies also plan to invest in other therapeutic areas, with 57% mentioning cell therapies (up 41% in 2020) and 56% targeting immunotherapies (up 32% in 2020).14
What will the future bring for clinical trials and, ultimately, FDA approval?
Because the pandemic is ongoing, it’s unclear which changes—if any—will become permanent fixtures in the FDA approval process.
Several trends have already emerged to speed new drug development; with clinical trials, researchers have learned many lessons about patient enrollment, targeting, and remote monitoring.
Of course, the ultimate question is: Will these gains in speed remain without affecting safety after the pandemic ends?
There are signs that at least some of the trends may endure.
The trend toward technology playing a larger role in medical testing has only grown and has been used more frequently for clinical trial optimization.
Other trends include the increased use of biomarkers and better use of data analytics. In addition, artificial intelligence/machine learning, or AIML, can be applied to real-world data such as electronic health records, laboratory test results, and insurance claims to ensure that trial design and patient recruitment reflect actual conditions.15
Some see the expedited process that began with CTAP as a potential improvement. However, it would most likely require an increase in FDA resources for expansion. Virtual meetings could remain part of the FDA landscape, as well, especially if accelerated approval is in the works.
However, there’s also concern that some of the relaxed data requirements, such as fewer regular physical inspections and remote clinical trials, could both undermine the safety of clinical participants and hinder the approval process.
It remains to be seen whether achievements during a time of crisis can be sustained after the pandemic and move into mainstream bio/pharmaceutical development.
References
2. Pharmacy Times. How the COVID-19 pandemic has impacted the FDA’s approval process. Pharmacy Times. Accessed September 3, 2021. https://www.pharmacytimes.com/view/how-the-covid-19-pandemic-has-impacted-the-fda-s-approval-process
3. Sharp J, Kenyatta K. The cost of speed: FDA regulatory flexibilities during the coronavirus pandemic. Commonwealth Fund. Accessed September 3, 2021. https://www.commonwealthfund.org/blog/2020/fda-regulatory-flexibilities-during-coronavirus-pandemic
4. Wechsler J. FDA inspection shutdown increasingly delays approvals. PharmTech. Accessed September 3, 2021. https://www.pharmtech.com/view/fda-inspection-shutdown-increasingly-delays-approvals
5. McDermott MM, Newman AB. Remote research and clinical trial integrity during and after the coronavirus pandemic. JAMA Network. Accessed September 3, 2021. https://jamanetwork.com/journals/jama/fullarticle/2779364?widget=personalizedcontent&previousarticle=2763819
6. US Food and Drug Administration. Conduct of clinical trials of medical products during the COVID-19 public health emergency. US Food and Drug Administration. Accessed September 3, 2021. https://www.fda.gov/media/136238/download
7. Rome BN, Avorn J. Drug evaluation during the Covid-19 pandemic. NEJM. Accessed September 3, 2021. https://www.nejm.org/doi/10.1056/NEJMp2009457?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
8. RIS.WORLD. USA – FDA approves 29 new drugs so far this year. RIS.WORLD. Accessed September 3, 2021. https://www.ris.world/usa-fda-approves-29-new-drugs-so-far-this-year/
9. US Food and Drug Administration. Understanding the regulatory terminology of potential preventions and treatments for COVID-19. US Food and Drug Administration. Accessed September 3, 2021. https://www.fda.gov/consumers/consumer-updates/understanding-regulatory-terminology-potential-preventions-and-treatments-covid-19
10. Iwry J. From 9/11 to COVID-19: a brief history of FDA emergency use authorization. Bill of Health. Accessed September 3, 2021. https://blog.petrieflom.law.harvard.edu/2021/01/28/fda-emergency-use-authorization-history/
11. Sherkow JS, Ouellette LL, Price N, Sachs R. What’s the difference between vaccine approval (BLA) and authorization (EUA)? Bill of Health. Accessed September 3, 2021. https://blog.petrieflom.law.harvard.edu/2021/06/15/whats-the-difference-between-vaccine-approval-bla-and-authorization-eua/
12. US Food and Drug Administration. Emergency use authorization for vaccines explained. US Food and Drug Administration. Accessed September 17, 2021. https://www.fda.gov/vaccines-blood-biologics/vaccines/emergency-use-authorization-vaccines-explained
13.Maragakis L, Kelen G. Full FDA approval of a COVID-19 vaccine: what you should know. Johns Hopkins Medicine. Accessed September 3, 2021. https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/full-fda-approval-of-a-covid-19-vaccine-what-you-should-know
14. BDO. 2021 Life sciences CFO outlook survey. BDO United States. Accessed September 3, 2021. https://www.bdo.com/insights/industries/life-sciences/2021-life-sciences-cfo-outlook-survey
15. Shanley A. Drug developers put pedal to the metal. PharmTech. Accessed September 3, 2021. https://www.pharmtech.com/view/drug-developers-put-pedal-to-the-metal
Please provide a valid e-mail address below to receive updates when new Blog content is available.
