The effort to develop therapeutics and vaccines to defend against COVID-19 has progressed at warp speed, if you will. As of March 8, 2021 — just over 13 months since then-HHS Secretary Alex Azar declared a public health emergency for the U.S. — the FDA already had given three vaccines, almost 10 drugs and biologics and 345 in vitro diagnostic tests Emergency Use Authorization (EUA). Industry experts suggest there are some lessons to be learned from the pandemic that the agency may leverage in the approval process overall.
The FDA has two ways that it can speed up use of medical countermeasures for serious illnesses, says Linda Garner, an information scientist at CAS, a division of the American Chemical Society that specializes in scientific information: the Expanded Access Program (EAP) and EUA. “The EAP allows for the compassionate use of unapproved (investigational) drugs without the need of detailed clinical trials when no satisfactory alternative therapy is available.”
In order to issue an EUA, explains Nancy Dreyer, Ph.D., chief scientific officer at IQVIA Real World Solutions, “the FDA must determine that it is reasonable to believe that a given product ‘may be effective’ as an emergency countermeasure to diagnose, treat or prevent serious or life-threatening diseases or conditions when certain statutory criteria have been met. These criteria include a determination that there are no adequate, approved and available alternatives. The known and potential benefits of authorization must outweigh the known and potential risks.”
“Manufacturers and laboratories submit an EUA for their product, and approval can be based on laboratory animal efficacy data with little clinical information,” says Garner. “When sufficient evidence that the unapproved (investigational) drug is safe becomes available, the product can transition from EAP to EUA, as was the case with convalescent plasma, a COVID-19 therapeutic agent, in 2020.”
Still required before approval are phase I, II and III clinical trials “to evaluate common short-term side effects and risks, and to examine the relationship between the dose administered and the immune response,” explains Dreyer.
In addition, the FDA can implement additional EUA guidelines for drugmakers and labs, points out Garner, citing COVID serological diagnostic tests “wherein the FDA outlined the sensitivity and specificity requirements of tests needed before they would be considered for approval and in the case of vaccines wherein the FDA outlined clinical data required before vaccines would be approved.” The agency also can revoke an EUA, as it did with hydroxychloroquine and chloroquine last year less than three months after issuing an EUA for the drugs.
“If clinical data supports both the safety and the efficacy of the drug or product, the FDA can authorize a final approval,” she states, pointing to Gilead Sciences, Inc.’s remdesivir as an example. “Remdesivir was granted EUA for treating COVID-19 patients in the hospital on May 1, 2020, [and] its EUA was updated/reissued on Aug. 28, 2020.” Then on Oct. 22, 2020, the FDA approved the drug as Veklury through its Coronavirus Treatment Acceleration Program for treating people at least 12 years old and weighing at least 40 kg who require hospitalization.
Garner tells AIS Health that the EUA and EAP processes “have been in existence, in various forms, for decades. The FDA has previously granted EUAs for diagnostic tests for viruses known to cause serious diseases such as Zika, Ebola and Middle East Respiratory Syndrome (MERS). The FDA has also previously provided EUA authorization for vaccines, such as the vaccine for anthrax.”
According to Dreyer, “this EUA process was a logical response to lessons learned from previous pandemic threats. For example, in 1976 President Gerald Ford pushed for a first-ever national vaccination program in preparation for the threat of a swine flu pandemic. Much was learned from that experience even though a swine flu pandemic never materialized, and many believed that a national vaccination program was an overreaction.
“The AIDS crisis gave further impetus to the EUA process since, as promising drugs were being developed, there was a strong public outcry to permit early use of these new treatments since there were no known effective treatments,” she continues. “However, it was the War on Terror and the aftermath of the events of Sept. 11, 2001, including anthrax mail attacks, that laid the groundwork for congressional approval of the Project BioShield Act of 2004. This allowed FDA formally to authorize unapproved products for emergency use against a threat to public health and safety (subject to a declaration of emergency by HHS).”
But although the FDA has used these mechanisms before, “the speed at which the FDA reviewed and approved the EAPs, EUAs and final approval related to COVID-19 was unprecedented due to the severity and widespread impact of this disease,” maintains Garner.
“A similar approach could really be applied to any therapeutic area,” she asserts. “However, these extraordinary measures are most likely to be used to address diseases that pose a high risk of mortality or severe damage to a large population and for which urgent intervention is anticipated to have significant benefit. Viruses are one of the most likely pathogens to present those circumstances, but potentially some biological warfare agents or common bacteria that become resistant to current antibiotics could at some point create an urgent need that I could imagine this applying to as well.”
The FDA’s role, however, goes beyond approving these products at an expedited rate. “While it is certainly important to get safe and effective vaccines to market as quickly as possible and to learn what treatments can reduce the severity of COVID-19 infections, it is also important to pay attention to what is required to build public comfort and confidence in these new vaccines and treatments,” Dreyer says. “While we clearly have had challenges with vaccine distribution, there also seems to be a paucity of information available about how these new vaccines are performing — on their own, compared to other vaccines and compared to the experience of the unvaccinated.”
“It is also important to highlight the effort by the FDA to protect consumers from fraudulent or unproven products that often emerge by those trying to take advantage of panic and high demand in times of crisis,” states Garner. “One area where this quickly became an issue was COVID-19 diagnostic kits. The FDA can set additional guidelines for manufacturers/laboratories submitting EUA for their products such as those for diagnostic tests and vaccines. In 2020, the FDA established the Operation Quack Hack for identifying fraudulent and unproven medical products related to COVID-19. This led domain registrars and online marketplaces to review and take down numerous websites or listings illegally selling unproven products.”
The COVID-19 pandemic obviously is a bit of an anomaly. A longtime industry expert who asked to remain unidentified paraphrases comments made by Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, that highlight two important factors in the accelerated vaccine development process: “The [virus’ genomic] sequence could be shared. Nobody was waiting on growing the virus, and [the sequence] could be shared essentially instantaneously worldwide. You know the one universal language we’ve still got is science, and so everybody in the globe had that sequence,” and that, in turn, “collapsed the whole idea of having to grow the virus and all the risks and stuff associated with that because you would have had biosafety containment and God knows what else.…It was key that we knew what SARS-CoV-2 was and what we were up against. The
other one was that the biggest aspect of the risk was actually financial in doing scale up concurrently with development.”
Still, the experience has the potential to have a broader impact on the development of non-COVID therapeutics, vaccines and tests.
“The effort to develop a COVID-19 vaccine has truly demonstrated our global pharma innovation capability when focused on a single priority,” says Todd Wills, managing director of consulting services at CAS. “Not only are the vaccine candidates themselves novel, but the focus in this area has accelerated progress on new and more efficient drug delivery platforms and processes that will pay dividends in other therapeutic areas as well. For example, many of the front-runners have resulted from novel collaborations between Big Pharma and smaller organizations, and several of the leading vaccine candidates are messenger-RNA vaccines, which is a relatively new delivery platform that has gotten a tremendous boost from COVID-19 vaccine research. There are also opportunities to apply lessons learned from the accelerated COVID-19 vaccine approval process to expedite FDA reviews and approvals in other critical areas.”
Wills tells AIS Health that “if some of the process efficiencies that were exercised to streamline clinical trials and regulatory processes for COVID therapies are able to be scaled more broadly, this could…lead to an increase in the total volume of approvals in years to come as well.”
The FDA has been working with regulatory agencies from six other countries to assess oncology drugs through Project Orbis, established in January 2017 by the agency’s Oncology Center of Excellence. Manufacturers submit applications for innovative therapies to multiple agencies for concurrent review. Participants are Australia’s Therapeutic Goods Administration, Canada’s Health Canada, Singapore’s Health Sciences Authority, Switzerland’s Swissmedic, Brazil’s Agencia Nacional de Vigilancia Sanitaria and the United Kingdom’s Medicines & Healthcare Products Regulatory Agency.
In addition, the FDA and European Medicines Agency have a mutual recognition agreement for inspections of manufacturing sites for certain medicines.
These programs may be a sign of things to come with respect to regulatory reliance following our experience with the pandemic. “This principle enables leveraging the output of others whenever possible while placing a greater focus at the national level on value-added regulatory activities that cannot be undertaken by other authorities, such as in-country vigilance activities and oversight of local manufacturing and distribution,” says the World Health Organization, noting that, “regulatory systems can be very resource-intensive.”
In a September 2020 forum by the National Academies of Sciences, Engineering, and Medicine on regulatory reliance, a speaker maintained that COVID has underscored the necessity of reliance among regulators: “People, disease and medicines cross borders,” and people around the world want similar access to therapies. “After COVID, [it’s] clear that mutual reliance among regulators is essential and urgent.”
According to the anonymous source, “this idea that COVID moves regulatory reliance forward by a significant step should be blindingly obvious, and then you’re leveraging cost, so this is another way the U.S. market could become more open to products that have exactly the same quality as if they’d had to go through every step in FDA.” The source acknowledges that some may consider that “heresy, but as a scientific and clinical matter, it is self-evidently necessary.”
“Does the FDA have an opportunity to say we’re going to do things wholly differently because of what we learned?” asks the unidentified source. “I think there are huge opportunities for the FDA, but they’re going to have to recover” from the siege the agency was under from the previous administration and its COVID “junk science,” to quote Vanity Fair. “I think [former FDA Commissioner Stephen] Hahn [M.D.] had the job from hell. To his credit he didn’t quit, and ultimately he stepped up and protected the agency.…The level of political damage is quite sad, but it’s not irrecoverable from.”
The source also maintains that the pharmaceutical industry needs to “get its sh-t together” and points to FDA submissions that are literally more than 1 million pages that the agency must read in their entirely. “In some cases [manufacturers are] doing that as a barrier to competition, so this is not solely an FDA responsibility.…There’s a complicity here that’s not necessarily bad but it’s conservative with a small c. But the opportunity is huge. It shouldn’t have taken COVID to make that opportunity, but if we’re going to suffer from COVID, let’s take it.”